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Hieromnimon M, Regan DP, Lokken RP, Schook LB, Gaba RC, Schachtschneider KM. Single and multi-omic characterization of a porcine model of ethanol-induced hepatic fibrosis. Epigenetics 2025; 20:2471127. [PMID: 40040391 PMCID: PMC11901410 DOI: 10.1080/15592294.2025.2471127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 02/10/2025] [Accepted: 02/18/2025] [Indexed: 03/06/2025] Open
Abstract
Cirrhosis is a form of end-stage liver disease characterized by extensive hepatic fibrosis and loss of liver parenchyma. It is most commonly the result of long-term alcohol abuse in the United States. Large animal models of cirrhosis, as well as of one of its common long-term sequelae, HCC, are needed to study novel and emerging therapeutic interventions. In the present study, liver fibrosis was induced in the Oncopig cancer model, a large animal HCC model, via intrahepatic, intra-arterial ethanol infusion. Liver sections from five fibrosis induced and five age-matched controls were harvested for RNA-seq (mRNA and lncRNA), small RNA-seq (miRNA), and reduced representation bisulfite sequencing (RRBS; DNA methylation). Single- and multi-omic analysis was performed to investigate the transcriptomic and epigenomic mechanisms associated with fibrosis deposition in this model. A total of 3,439 genes, 70 miRNAs, 452 lncRNAs, and 7,715 methylation regions were found to be differentially regulated through individual single-omic analysis. Pathway analysis indicated differentially expressed genes were associated with collagen synthesis and turnover, hepatic metabolic functions such as ethanol and lipid metabolism, and proliferative and anti-proliferative pathways including PI3K and BAX/BCL signaling pathways. Multi-omic latent variable analysis demonstrated significant concordance with the single-omic analysis. lncRNA's associated with UHRF1BP1L and S1PR1 genes were found to reliably discriminate the two arms of the study. These genes were previously implicated in human cancer development and vasculogenesis, respectively. These findings support the validity and translatability of this model as a useful preclinical tool in the study of alcoholic liver disease and its treatment.
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Affiliation(s)
- Mark Hieromnimon
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Daniel P. Regan
- Flint Animal Cancer Center, Colorado State University, Fort Collins, CO, USA
| | - R. Peter Lokken
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
| | - Lawrence B. Schook
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Sus Clinicals Inc, Chicago, IL, USA
| | - Ron C. Gaba
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Kyle M. Schachtschneider
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Sus Clinicals Inc, Chicago, IL, USA
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
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Zhu JF, Wang YQ, Yang SM, Wang YL, Hu Y, Dai XY. Exploring the mechanism of Bruceine D against cervical cancer by network pharmacology and the effect of Bruceine D on the EGFR pathway. J Pharm Biomed Anal 2025; 262:116887. [PMID: 40239560 DOI: 10.1016/j.jpba.2025.116887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/25/2025] [Accepted: 04/08/2025] [Indexed: 04/18/2025]
Abstract
Cervical cancer (CC) remains a formidable challenge in oncology due to its high incidence and mortality rates. Despite recent advances in treatment, an immediate necessity exists for innovating advanced pharmacological interventions boasting augmented effectiveness. Bruceine D (BD), a quassinoid derived from the traditional Chinese medicinal plant Brucea javanica, has been demonstrated to possess notable anticancer properties against a range of malignant conditions, including lung, liver, leukemia, and pancreatic cancers. However, its specific effects on CC have not been thoroughly explored. This study sought to decode the effects of BD on CC through a combined method involving molecular docking analysis, network pharmacology, and data mining. From the PharmMapper database, we identified 58 potential targets of BD, and through GeneCards, we pinpointed 14 intersecting targets relevant to CC. A protein-protein interaction (PPI) network highlighted pivotal targets such as ESR1, HSP90AA1, ANXA5, EGFR, CASP7, and CCNA2. GO and KEGG enrichment analyses underscored significant biological processes and pathways, notably the EGFR signaling pathway. Molecular docking analysis revealed a strong binding affinity of BD to EGFR. Cell-based assays demonstrated that BD potently curtailed the viability, colony formation, adhesion, and mobility of Hela and Caski cells, escalating apoptosis in a dose-proportional manner. Supplementary evidence via western blot evaluations underscored BD's capability to obstruct the EGFR signaling pathway. These findings suggest that BD exerts potent anticancer effects against CC through multiple mechanisms, positioning it as a promising therapeutic agent for further investigation and clinical validation.
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Affiliation(s)
- Ju-Fan Zhu
- Institute of Organoid Technology, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Yuan-Qiu Wang
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Si-Meng Yang
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yu-Li Wang
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yan Hu
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
| | - Xin-Yue Dai
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
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Wu W, Wang X, Ma R, Huang S, Li H, Lyu X. Deciphering the roles of neddylation modification in hepatocellular carcinoma: Molecular mechanisms and targeted therapeutics. Genes Dis 2025; 12:101483. [PMID: 40290125 PMCID: PMC12022649 DOI: 10.1016/j.gendis.2024.101483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 08/05/2024] [Accepted: 11/02/2024] [Indexed: 04/30/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent type of malignant liver tumor with high morbidity and mortality and severely threatens human health and life quality. Thus, it is of great significance to investigate the molecular mechanism underlying the pathogenesis of HCC and seek biomarkers for early diagnosis. Neddylation, one of the most conserved post-translational modification types in eukaryotes, plays vital roles in the progression of HCC. During the process of neddylation, NEDD8 is covalently conjugated to its substrate proteins, thereby modulating multiple necessary biological processes. Currently, increasing evidence shows that the aberrant activation of neddylation is positively correlated with the occurrence and development of tumors and the poor clinical prognosis of HCC patients. Based on the current investigations, neddylation modification has been reported to target both the cullins and non-cullin substrates and subsequently affect HCC progression, including the virus infection, malignant transformation, tumor cell proliferation, migration and invasion ability, and tumor microenvironment. Therefore, inhibitors targeting the neddylation cascade have been developed and entered clinical trials, indicating satisfactory anti-HCC treatment effects. This review aims to summarize the latest progress in the molecular mechanism of pathologically aberrant neddylation in HCC, as well as the advances of neddylation-targeted inhibitors as potential drugs for HCC treatment.
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Affiliation(s)
- Wenxin Wu
- School of Clinical and Basic Medical Sciences, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250117, China
| | - Xuanyi Wang
- School of Clinical and Basic Medical Sciences, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250117, China
| | - Ruijie Ma
- Department of Thoracic Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Shuhong Huang
- School of Clinical and Basic Medical Sciences, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250117, China
- Science and Technology Innovation Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250117, China
| | - Hongguang Li
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Xinxing Lyu
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong 250117, China
- School of Clinical and Basic Medical Sciences, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250117, China
- Science and Technology Innovation Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250117, China
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Zhang X, Shao W, Gao Y, Wang X. Macrophage polarization-mediated PKM2/mTORC1/YME1L signaling pathway activation in fibrosis associated with Cardiorenal syndrome. Cell Signal 2025; 131:111664. [PMID: 39961408 DOI: 10.1016/j.cellsig.2025.111664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/16/2024] [Accepted: 02/14/2025] [Indexed: 04/04/2025]
Abstract
BACKGROUND Cardiorenal syndrome (CRS) is a complex condition characterized by the interplay between cardiac and renal dysfunction, often culminating in renal fibrosis. The role of macrophage polarization and its downstream effects in CRS-induced renal fibrosis remains an area of active investigation. METHODS Single-cell RNA sequencing (scRNA-seq) and immune infiltration analyses were employed to identify key immune cells and genes involved in renal fibrosis in CRS. Meta-analysis and pseudo-time analysis were conducted to validate the functional relevance of these genes. Functional studies utilizing CRISPR/Cas9 gene editing and lentiviral vectors assessed macrophage polarization and epithelial-to-mesenchymal transition (EMT). In vivo, a CRS mouse model was established, and fibrosis progression was tracked using histological and imaging methods. RESULTS The PKM2/mTORC1/YME1L signaling axis was identified as a critical pathway driving renal fibrosis, mediated by HIF-1α-induced M1 macrophage polarization. Inhibition of HIF-1α significantly alleviated renal fibrosis by restricting M1 polarization and suppressing the PKM2/mTORC1/YME1L axis. Co-culture models further demonstrated the involvement of EMT and metabolic reprogramming in affected cells. CONCLUSION Targeting the HIF-1α signaling pathway offers a promising therapeutic strategy for renal fibrosis by modulating macrophage polarization and the PKM2/mTORC1/YME1L axis.
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Affiliation(s)
- Xuefeng Zhang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, China.
| | - Wen Shao
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Yun Gao
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Xiaojun Wang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, China
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Zhou H, Lao M, Liang Z, Zhao H, Wang Y, Huang Q, Ou C. Identification of M0 macrophage associated lipid metabolism genes for prognostic and immunotherapeutic response prediction in hepatocellular carcinoma. Discov Oncol 2025; 16:781. [PMID: 40377731 DOI: 10.1007/s12672-025-02620-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 05/08/2025] [Indexed: 05/18/2025] Open
Abstract
PURPOSE Liver cancer prognosis is associated with M0 macrophages and lipid metabolism reprogramming; however, the prognostic role of M0 macrophage-related lipid metabolism genes in hepatocellular carcinoma (HCC) remains unclear. METHODS We identified 153 lipid metabolism genes associated with M0 macrophage infiltration in HCC from The Cancer Genome Atlas (TCGA) and the Molecular Signatures Database (MSigDB). Prognostic genes were selected, and a model was constructed using least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. The model was validated using the International Cancer Genome Consortium (ICGC) database. We assessed the expression levels of prognostic genes by quantitative real-time polymerase chain reaction (qRT‒PCR). RESULTS A prognostic model was developed based on five characteristic genes. Receiver operating characteristic curve analysis demonstrated that the model had good accuracy, with area under the curve values of 0.796, 0.732, and 0.728 for predicting survival at 1, 3, and 5 years, respectively. The high-risk group exhibited increased sensitivity to common chemotherapy drugs, including sorafenib, dasatinib, and 5-fluorouracil, compared with the low-risk group (P < 0.05). Additionally, the high-risk group had significantly more infiltrating M0 macrophages, resting dendritic cells, follicular helper T cells, and regulatory T cells than did the low-risk group (P < 0.05). The qRT‒PCR results confirmed the upregulation of these five characteristic genes in HCC tissues. CONCLUSIONS M0 macrophage-associated lipid metabolism genes may serve as biomarkers for the prognosis of patients with HCC and as targets for immunotherapy.
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Affiliation(s)
- Huanjie Zhou
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Ming Lao
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Zhengui Liang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Huiliu Zhao
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Ying Wang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Qiongqing Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Chao Ou
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China.
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Wang X, Zhong W, Wang Q, Song P, Lin X, Li B, Yin Y, Yang C, Li M. Lysionotin promoted apoptosis of hepatocellular carcinoma cells via inducing autophagy. Discov Oncol 2025; 16:788. [PMID: 40377756 DOI: 10.1007/s12672-025-02503-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 04/25/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma is a prevalent malignant tumor with a high mortality rate. Natural plants hold promise for its treatment, however, the mechanism of lysionotin induced apoptosis in liver cancer cells unclearly. This study aims to investigate the microenvironment alterations and the efficacy of lysionotin in liver cancer. METHODS Transmission electron microscopy, and laser confocal microscopy were employed to investigate the effect of lysionotin on autophagy in HCC cells. The molecular mechanism through which lysionotin induces autophagy and autophagy-induced apoptosis was ascertained by transcriptome sequencing, immunoblotting and Hoechst 33258 staining. RESULTS RNA sequencing analysis, electron microscopy and laser confocal microscopy revealed that lysionotin initiate autophagy in liver cancer cells. Immunoblotting indicated that lysionotin markedly enhances the activation of LC3-II in HCC cells, resulting in the activation of key effector molecules ATG12, Beclin-1 and the degradation of P62. Combined with autophagy inhibitors CQ and 3-MA significantly inhibited lysionotin-induced cell apoptosis. Immunoblotting and Hoechst staining disclosed that the activation of autophagy by lysionotin might be associated with the suppression of the mTOR-AKT signaling pathway. The treatment of mTOR inhibitor RAPA and activator 1485 demonstrated that inhibiting mTOR activation significantly augments the pro-apoptotic effect of lysionotin on liver cancer cells, while mTOR activator could rescue the effect of lysionotin on cells. CONCLUSIONS The findings suggest that the activation of autophagy by lysionotin may represent one of the pivotal mechanisms underlying its therapeutic efficacy against HCC and its synergistic enhancement of RAPA's antitumor effects.
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Affiliation(s)
- Xiaoxue Wang
- School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China
| | - Weiwei Zhong
- School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China
| | | | - Peng Song
- School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China
| | - Xia Lin
- School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China
| | - Bohan Li
- School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China
| | - Yancun Yin
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, People's Republic of China
| | - Chunyan Yang
- School of Stomatology, Binzhou Medical University, Yantai, Shandong, People's Republic of China
| | - Minjing Li
- School of Traditional Chinese Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China.
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Zeng Y, Tao Y, Du G, Huang T, Chen S, Fan L, Zhang N. Advances in the mechanisms of HIF-1α-enhanced tumor glycolysis and its relation to dedifferentiation. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025:S0079-6107(25)00024-0. [PMID: 40373959 DOI: 10.1016/j.pbiomolbio.2025.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 05/07/2025] [Accepted: 05/12/2025] [Indexed: 05/17/2025]
Abstract
Metabolic reprogramming, a hallmark of malignancy, enables tumor cells to adapt to the harsh and dynamic tumor microenvironment (TME) by altering metabolic pathways. Hypoxia, prevalent in solid tumors, activates hypoxia inducible factor 1α (HIF-1α). HIF-1α drives metabolic reprogramming, enhancing glycolysis primarily through the Warburg effect to reduce oxygen dependence and facilitate tumor cell growth/proliferation. The above process is associated with accelerated tumor cell dedifferentiation and enhanced stemness, generating cancer stem cells (CSCs) which possesses the potential for self-renewal and differentiation that can differentiate into a wide range of subtypes of tumor cells and fuel tumor heterogeneity, metastasis, and recurrence, complicating therapy. This review examines the HIF-1α-glycolysis-dedifferentiation crosstalk mechanisms, expecting that indirect inhibition of HIF-1α by targeting metabolic enzymes, metabolites, or their signaling pathways will offer an effective therapeutic strategy to improve the cancer treatment outcomes.
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Affiliation(s)
- Yu Zeng
- Zunyi China, The Affiliated Hospital of Zunyi Medical University(1)
| | - Yonggang Tao
- Zunyi China, The Affiliated Hospital of Zunyi Medical University(1)
| | - Guotu Du
- Zunyi China, The Affiliated Hospital of Zunyi Medical University(1)
| | - Tianyu Huang
- Zunyi China, The Affiliated Hospital of Zunyi Medical University(1)
| | - Shicheng Chen
- Zunyi China, The Second Affiliated Hospital of Zunyi Medical University(2)
| | - Longmei Fan
- Zunyi China, The Affiliated Hospital of Zunyi Medical University(1)
| | - Neng Zhang
- Zunyi China, The Affiliated Hospital of Zunyi Medical University(1).
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Zhou Y, Wang F, Feng S, Li M, Zhu M. USP39 promote post-translational modifiers to stimulate the progress of cancer. Discov Oncol 2025; 16:749. [PMID: 40358671 PMCID: PMC12075731 DOI: 10.1007/s12672-025-02573-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
Deubiquitinating enzymes (DUBs) are a class of crucial peptidyl hydrolases within the ubiquitin system, playing a significant role in reversing and strictly regulating ubiquitination, which is essential for various biological processes such as protein stability and cellular signal transduction. Ubiquitin-specific protease 39 (USP39) is an important member of the DUBs family. Recent studies have revealed that USP39 is involved in the regulation of multiple cellular activities including cell proliferation, migration, invasion, apoptosis, and DNA damage repair. USP39 also plays a significant role in the development and progression of various cancers. It is believed that USP39 is a unique enzyme that controls the ubiquitin process and is closely associated with the occurrence and progression of many cancers, including hepatocellular, lung, gastric, breast, and ovarian cancer. This review summarizes the structural and functional aspects of USP39 and its research advancements in tumors, investigates the key molecular mechanisms related to USP39, and provides references for tumor diagnosis and treatment.
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Affiliation(s)
- Yuli Zhou
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Fang Wang
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Siren Feng
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China
| | - Mengsen Li
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China.
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical University, Haikou, 570216, China.
| | - Mingyue Zhu
- Key Laboratory of Tropical Translational Medicine, Ministry of Education and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, 3 Xueyuan Road, Longhua District, Haikou, 571199, Hainan, People's Republic of China.
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Wang Z, Sheng J, Zhang X. Characterization of adverse reactions to four common targeted drugs for hepatocellular carcinoma in WHO-VigiAccess. Sci Rep 2025; 15:16188. [PMID: 40346128 PMCID: PMC12064674 DOI: 10.1038/s41598-025-00004-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 04/24/2025] [Indexed: 05/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality, with limited therapeutic options available for advanced stages of the disease. Treatment strategies for HCC are multimodal and largely depend on the disease stage, liver function, and individual patient factors. Based on the WHO's VigiAccess database, this study employed a retrospective descriptive analysis of adverse drug reaction (ADR) reports associated with four widely used tyrosine kinase inhibitors (TKIs) for HCC, including Sorafenib, Cabozantinib, Lenvatinib, and Regorafenib. The analysis included demographic data such as patient age, gender, and geographical distribution, alongside clinical information on the systems and symptoms associated with ADR reports. A total of 112,975 ADR reports related to the four TKI-targeted drugs were identified. Sorafenib exhibited the highest ADR reporting rate (30.7%), followed by Cabozantinib (29.4%), Lenvatinib (24.5%), and Regorafenib (15.4%). The odds ratio method was employed to assess the statistical correlation between the use of these targeted drugs and the occurrence of ADRs. Notably, Sorafenib (3,746) and Regorafenib (2,496) served to have the highest number of reported palmar-plantar erythrodysaesthesia syndrome. Chi-square analyses suggested that ADRs related to Lenvatinib were reported significantly more frequently in female patients compared to their male counterparts. The findings of this study can enhance public awareness of drug-related adverse events and provide an evidence-based foundation for prioritizing the management of ADRs associated with TKIs in second-line HCC therapy.
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Affiliation(s)
- Zeyu Wang
- Department of the Hepatobiliary and Pancreatic Surgery, Jilin University Second Hospital, Changchun, 130000, China
| | - Jiyao Sheng
- Department of the Hepatobiliary and Pancreatic Surgery, Jilin University Second Hospital, Changchun, 130000, China.
| | - Xuewen Zhang
- Department of the Hepatobiliary and Pancreatic Surgery, Jilin University Second Hospital, Changchun, 130000, China.
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10
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Zhang C, Zhou Y, Hu M, Pan Y, Chen X, Sun Q, Ma Z, Wang C, Zha Y, Zhu F, Xia H. PLOD1 promotes the malignancy of hepatocellular carcinoma by facilitating the NF-κB/IL-6/STAT3-dependent TCA cycle. JHEP Rep 2025; 7:101329. [PMID: 40290518 PMCID: PMC12023786 DOI: 10.1016/j.jhepr.2025.101329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 01/09/2025] [Accepted: 01/14/2025] [Indexed: 04/30/2025] Open
Abstract
Background & Aims Procollagen lysyl hydroxylase 1 (PLOD1) is crucial in regulating collagen synthesis and cross-linking. However, its roles and underlying mechanisms in the progression of hepatocellular carcinoma (HCC) remain unclear. Herein, we aimed to investigate the underlying biological functions and mechanisms of PLOD1 in HCC. Methods The expression levels of PLOD1 in HCC were measured by qPCR, Western blot, and immunohistochemistry. Cell proliferation, apoptosis, and stemness were examined by CCK8, flow cytometry, sphere formation, and aldehyde dehydrogenase activity assays. The subcutaneous tumorigenicity model, orthotopic tumorigenicity model, and hepatotoxin-induced HCC model were used for in vivo experiments. RNA-sequence and untargeted metabolomics analysis were performed to identify underlying mechanisms. Results PLOD1 is found to be highly expressed in both human (p <0.0001) and mouse HCC (p <0.01) and is associated with a poor prognosis (p = 0.047). In vitro and in vivo experiments reveal that overexpression of PLOD1 promotes the proliferation and stemness of HCC cells. Meanwhile, the depletion of PLOD1 attenuates the occurrence and growth of HCC, leading to cell cycle arrest (p <0.01) and apoptosis (p <0.001) in HCC. Mechanistically, PLOD1 positively regulates the NF-κB/IL-6/STAT3 signaling pathway and accelerates TCA cycle metabolic reprogramming. Blocking the NF-κB/IL-6/STAT3 signaling pathway and TCA cycle can effectively mitigate PLOD1-induced proliferation and stemness of HCC cells. Conclusions Our study uncovers the PLOD1/NF-κB/IL-6/STAT3 axis as a therapeutic target for inhibiting the progression and stemness of HCC. Impact and implications The roles and underlying mechanisms of PLOD1 in the progression of HCC remain unclear. In this study, we report that PLOD1 is highly expressed in patients with HCC and promotes the proliferation and stemness of HCC cells by activating the NF-κB/IL-6/STAT3-dependent TCA cycle. Knocking down hepatic PLOD1 using adeno-associated virus results in reduced progression of HCC in mice, suggesting that PLOD1 may serve as a potential therapeutic target for HCC.
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Affiliation(s)
- Chengfei Zhang
- Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
- Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing, China
- Department of Pathology, Nanjing Drum Tower Hospital & National Health Commission Key Laboratory of Antibody Techniques & School of Basic Medical Sciences of Nanjing Medical University, Nanjing, China
| | - Yangchun Zhou
- Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Minghua Hu
- Department of Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China
| | - Yue Pan
- Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Xin Chen
- Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Qi Sun
- Department of Pathology, Nanjing Drum Tower Hospital & National Health Commission Key Laboratory of Antibody Techniques & School of Basic Medical Sciences of Nanjing Medical University, Nanjing, China
| | - Zhijie Ma
- Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Cheng Wang
- Department of Pathology, Nanjing Drum Tower Hospital & National Health Commission Key Laboratory of Antibody Techniques & School of Basic Medical Sciences of Nanjing Medical University, Nanjing, China
| | - Yong Zha
- Hepatobiliary Pancreatic Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China
| | - Feng Zhu
- Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Hongping Xia
- Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing, China
- Department of Pathology, Nanjing Drum Tower Hospital & National Health Commission Key Laboratory of Antibody Techniques & School of Basic Medical Sciences of Nanjing Medical University, Nanjing, China
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11
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Gao G, Zhang X, Wang Z, Xu J, Wang J, Liu T, Xie Z. Multiscale insights into cornuside's effects on NAFLD: A cross-disciplinary integrating bioinformatics, computational chemistry, and machine learning. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156809. [PMID: 40344848 DOI: 10.1016/j.phymed.2025.156809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 04/07/2025] [Accepted: 04/25/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a complex metabolic disorder involving intertwined signaling pathways, posing challenges for targeted therapeutic interventions. Cornus Fructus (CF), a traditional medicinal herb, holds potential for NAFLD treatment, with cornuside (COR) identified as its primary active component. METHODS This study employed a cross-disciplinary approach, integrating bioinformatics, computational chemistry, and machine learning to uncover COR's therapeutic mechanisms with precision and depth. RESULTS Using bioinformatics-driven analysis, 27 core targets were identified, revealing that COR modulated critical metabolic and inflammatory pathways. COR mitigated insulin resistance by regulating the AKT/GSK3β axis, enhanced cholesterol metabolism through LXR signaling, promoted fatty acid oxidation via PPARα activation, and suppressed inflammation by inhibiting NF-κB signaling. These results highlighted COR's ability to orchestrate multi-pathway regulation essential for restoring metabolic homeostasis in NAFLD. Molecular docking and molecular dynamics (MD) simulations provided atomistic insights, demonstrating COR's stable and high-affinity interactions with key targets. Additionally, machine learning algorithms enhanced target identification and pathway prediction, improving the precision and efficiency of the discovery process. CONCLUSION This study offered multi-scale mechanistic insights into COR's therapeutic effects on NAFLD, bridging experimental pharmacology and computational methods. The integration of bioinformatics, molecular simulation, and machine learning established a comprehensive framework for drug discovery, positioning COR as a promising candidate for NAFLD therapy and guiding future development of precision interventions.
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Affiliation(s)
- Gai Gao
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China; School of Pharmacy, Minzu University of China, Beijing 100081, China
| | - Xiaowei Zhang
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Zhenzhen Wang
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Jiangyan Xu
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Jinghui Wang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China.
| | - Tongxiang Liu
- School of Pharmacy, Minzu University of China, Beijing 100081, China.
| | - Zhishen Xie
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China.
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12
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Wang Y, Wang H, Li Q, Zhang Y, Dai R, Wu J, Zhang Y, Zhang X, Zhao L, Liu J. Identification of Novel Cyclobutane-Based Derivatives as Potent Acetyl-CoA Carboxylase Allosteric Inhibitors for Nonalcoholic Steatohepatitis Drug Discovery. J Med Chem 2025; 68:8578-8599. [PMID: 40227434 DOI: 10.1021/acs.jmedchem.5c00259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025]
Abstract
Nonalcoholic steatohepatitis (NASH) has become a leading cause of liver fibrosis and hepatocellular carcinoma; however, there are no efficient drugs for NASH therapy. Acetyl-CoA carboxylase (ACC) is a crucial enzyme regulating lipid metabolism that is considered as a potential target for NASH treatment. Allosteric inhibitors target nonfunctional sites, which tend to be highly variable in protein families; thus, allosteric inhibitors are explored as an important source of drug candidates. Herein, several hotspot residues are initially identified by utilizing molecular dynamic simulation, MM-GBSA calculation, and alanine mutation. Then, focusing on the interaction with hotspot residues, several cyclobutane-based ACC allosteric inhibitors are designed, synthesized, and biologically evaluated. Among them, B1 demonstrates potent ACC inhibitory activity in vitro, a higher distribution in liver than in other tissues, and a potent therapeutic effect for NASH in vivo, making it a promising candidate for the treatment of NASH.
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Affiliation(s)
- Yazhou Wang
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Hai Wang
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Qingqing Li
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ying Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Rupeng Dai
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jun Wu
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Yanan Zhang
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Xiaomeng Zhang
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Liwen Zhao
- R & D Center, Nanjing Sanhome Pharmaceutical Co. Ltd., Nanjing 210049, China
| | - Jian Liu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- School of Artificial Intelligence and Information Technology, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
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13
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Mustafa AM, El-Shiekh RA, Esmail MM, Hassan E, Senna MM, Ebid N, Elgindy AM. Surveying the Therapeutic Potentials of Isoliquiritigenin (ISL): A Comprehensive Review. Chem Biodivers 2025:e202500456. [PMID: 40274535 DOI: 10.1002/cbdv.202500456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 04/26/2025]
Abstract
Isoliquiritigenin (ISL), a major chalcone-type flavonoid produced predominantly from liquorice roots (Glycyrrhiza species), has exceptional therapeutic potential across a wide range of pharmacological activities. ISL has numerous benefits including antioxidant, anti-inflammatory, antidiabetic, cardioprotective, hepatoprotective, neuroprotective, and anticancer activities. This review gathers the pharmacological effects of ISL remarking into its mechanism of actions such as how it modulates oxidative stress, inflammatory pathways, glucose metabolism, and cancer growth, demonstrating its pharmacological versatility. The review emphasizes new advances in the field, allowing for more rational development and clinical use of ISL in medicine. However, further research is required to confirm the target-organ toxicity or side-effect investigations.
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Affiliation(s)
- Aya M Mustafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Riham A El-Shiekh
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Manar M Esmail
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Eslam Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Mohamed Magdy Senna
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Nouran Ebid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Ali M Elgindy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
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14
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Yi F, Long S, Yao Y, Fu K. A Novel Signature Composed of Hypoxia, Glycolysis, Lactylation Related Genes to Predict Prognosis and Immunotherapy in Hepatocellular Carcinoma. FRONT BIOSCI-LANDMRK 2025; 30:33422. [PMID: 40302343 DOI: 10.31083/fbl33422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 03/17/2025] [Accepted: 03/21/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. The hypoxic microenvironment in HCC enhances glycolysis and co-directed lactate accumulation, which leads to increased lactylation. However, the exact biological pattern remains to be elucidated. Therefore, we sought to identify hypoxia-glycolysis-lactylation (HGL) prognosis-related signatures and validate this in vitro. METHODS Transcriptomic data of patients with HCC were collected from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. Differentially expressed HGL genes between HCC and normal tissues were obtained by DEseq2. The consensus clustering algorithm was employed to stratify patients into two distinct clusters. Subsequently, the single sample Gene Set Enrichment Analysis (ssGSEA), Tumor Immune Estimation Resource (TIMER) and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms were utilized to assess immune infiltration and immune evasion. Least Absolute Shrinkage and Selection Operator (LASSO) and COX regression analysis were used to identify an HGL prognosis-related signature. Based on spatial transcriptome and histological data, we analyzed the expression of these genes in HCC and explored the function of Homer Scaffold Protein 1 (HOMER1) in HCC cells. RESULTS We identified 72 differentially expressed HGL genes and two HGL clusters. Cluster2, with better survival (p < 0.001), was significantly enriched in metabolic-related pathways. The HGL prognosis-related signature exhibited great predictive efficacy for patients in TCGA, ICGC, and GSE148355 databases (3-year area under the curve (AUC) = 0.822, 0.738, and 0.707, respectively). The elevated expression of HOMER1 in HCC was revealed by the combination of spatial transcriptome and histological data. Knocking down HOMER1 significantly inhibited the malignant progression of HCC cells. CONCLUSIONS We identified a signature with great predictive efficacy and discovered a gene, HOMER1, that influences the malignant progression of HCC with the potential to become a novel therapeutic target.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/therapy
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/mortality
- Liver Neoplasms/genetics
- Liver Neoplasms/therapy
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms/immunology
- Liver Neoplasms/mortality
- Prognosis
- Glycolysis/genetics
- Immunotherapy
- Gene Expression Regulation, Neoplastic
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Tumor Microenvironment/genetics
- Transcriptome
- Gene Expression Profiling
- Cell Line, Tumor
- Female
- Male
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Affiliation(s)
- Feng Yi
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, 410083 Changsha, Hunan, China
| | - Shichao Long
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, 410083 Changsha, Hunan, China
- Department of Radiology, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410083 Changsha, Hunan, China
| | - Yuanbing Yao
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, 410083 Changsha, Hunan, China
| | - Kai Fu
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, 410083 Changsha, Hunan, China
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 410083 Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, 410114 Changsha, Hunan, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, 410083 Changsha, Hunan, China
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15
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Dai C, Tong Y, Bai N, Xu N, Zhao X, Zhou L, Tang Z, Liu M, Xu B, Liu X, Chen Y, Lin Z, Li J, Bian S, Zheng W. Decoding the role of nucleic acid binding protein 2 in lipid dysregulation and hepatocellular carcinoma progression through LKB1-mediated mitochondrial dysfunction. Cell Signal 2025; 132:111820. [PMID: 40250697 DOI: 10.1016/j.cellsig.2025.111820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/22/2025] [Accepted: 04/15/2025] [Indexed: 04/20/2025]
Abstract
Nucleic Acid Binding Protein 2 (NABP2), a crucial regulator in the single-stranded DNA-binding protein family, has been linked to the progression of hepatocellular carcinoma (HCC) and poor prognosis. However, the precise mechanisms by which NABP2 regulates HCC development, especially through metabolic pathways, remain unclear. In this study, we evaluated NABP2 expression in clinical HCC samples and analyzed its correlation with patient survival outcomes. Functional assays, including cell proliferation, migration, and lipid metabolism analyses, were performed in vitro and in vivo to investigate the role of NABP2 in tumorigenesis. Additionally, we examined the molecular interactions of NABP2 with the E3 ubiquitin ligase STUB1 and its impact on the LKB1/AMPK signaling pathway. Our results revealed that NABP2 was overexpressed in HCC tissues and associated with worse survival outcomes. NABP2 promoted tumor cell proliferation, migration, and disrupted lipid metabolism. Mechanistically, NABP2 regulated the proteostasis of liver kinase B1 (LKB1) by recruiting STUB1, leading to the inhibition of the LKB1/AMPK signaling axis and mitochondrial dysfunction. In conclusion, our findings suggest that NABP2 may serve as both a biomarker and a potential therapeutic target for HCC, offering novel insights into its role in metabolic reprogramming and tumor progression.
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Affiliation(s)
- Chengchen Dai
- Research Center of Clinical Medicine & Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Yun Tong
- Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Nan Bai
- Research Center of Clinical Medicine & Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Nuo Xu
- Research Center of Clinical Medicine & Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Xuying Zhao
- Research Center of Clinical Medicine & Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Lihua Zhou
- Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Zhangzhi Tang
- Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Mingyu Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Banglong Xu
- Research Center of Clinical Medicine & Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Xiaoquan Liu
- Research Center of Clinical Medicine & Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Yinqi Chen
- Research Center of Clinical Medicine & Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Zhaoyi Lin
- Research Center of Clinical Medicine & Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Jinlong Li
- College of Pharmacology, Nantong University, Nantong, China.
| | - Saiyan Bian
- Research Center of Clinical Medicine & Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
| | - Wenjie Zheng
- Research Center of Clinical Medicine & Department of Clinical and Translational Research Center, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Department of Pathology, Medical School of Nantong University, Nantong 226001, China.
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16
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Xu F, Qiu J, Liu N, Wei H, Gao Y, Fei Y, Xi J, Yu Z, Fan X, Chen L, Xia Y, Dou X. Therapeutic Potential of Raspberry Extract in High-Fat Diet-Induced Liver Injury via Apoptosis and AMPK/PPARα Pathways. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:9408-9423. [PMID: 40168586 DOI: 10.1021/acs.jafc.4c09593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/03/2025]
Abstract
This study aimed to explore the efficacy and mechanisms of raspberry (Rubus idaeus L. fruit) aqueous extract (RE) in alleviating high-fat diet (HFD)-induced metabolic-associated fatty liver disease (MAFLD). The MAFLD mouse model was established to examine the effects of RE through liver transcriptome and metabolomics analysis. In this study, RE supplementation significantly alleviated HFD-induced liver injury, hepatosteatosis, inflammation, and insulin resistance. Liver transcriptome analysis demonstrated that RE supplementation favorably regulated signaling pathways involved in fatty acid metabolism and inflammation, including the AMPK signaling pathway, PPAR signaling pathway, apoptosis, etc. Furthermore, the injection of compound C, an antagonist of AMPK, notably reversed the hepatoprotective effects of RE, evidenced by increased lipid profile levels, accelerated fatty acid-related gene disorder, and increased positive tunnel staining area. Furthermore, liver metabolomics analysis demonstrated that RE treatment led to substantial enrichment of the liver tissue metabolite umbelliferone (UMB), which has the potential to ameliorate lipid accumulation and hepatocyte injury through the AMPK signaling pathway. In summary, RE intervention mitigated HFD-induced liver dysfunction in mice, with UMB likely being the primary component responsible for its therapeutic efficacy in the liver. In addition, this study provided new insights, suggesting that RE could be used as a promising therapeutic approach for modulating MAFLD via apoptosis and the AMPK/PPARα signaling pathway.
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Affiliation(s)
- Fangying Xu
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, China
| | - Jiannan Qiu
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, China
| | - Nian Liu
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, China
| | - Huaxin Wei
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, China
| | - Yanyan Gao
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, China
| | - Yang Fei
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, China
| | - Jiale Xi
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, China
| | - Zhiling Yu
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 852, China
| | - Xiaohui Fan
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Lin Chen
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, China
| | - Yongliang Xia
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, China
| | - Xiaobing Dou
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, China
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Miao YR, Yang XJ. Hepatocellular carcinoma resistance to tyrosine kinase inhibitors: Current status and perspectives. World J Gastrointest Oncol 2025; 17:101528. [PMID: 40235904 PMCID: PMC11995346 DOI: 10.4251/wjgo.v17.i4.101528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/31/2024] [Accepted: 01/08/2025] [Indexed: 03/25/2025] Open
Abstract
The study conducted by Wang et al, focuses on the role of Rho GTPase activating protein 12 (ARHGAP12), in hepatocellular carcinoma (HCC). This research reveals that ARHGAP12 expression, markedly elevated in malignant cells of HCC, correlates strongly with adverse outcomes for patients. Furthermore, the study illustrates that ARHGAP12 enhances the ability of HCC cells to invade and contributes to their resistance to tyrosine kinase inhibitors (TKIs) through modulation of the focal adhesion pathway. To comprehensively investigate the relationship between ARHGAP12 and TKI resistance, this study integrates single-cell and bulk RNA sequencing methodologies along with data from tumor immune single-cell hub 2, Gene Expression Omnibus, The Cancer Genome Atlas, CellMiner, Genomics of Drug Sensitivity in Cancer 2, as well as immunohistochemical staining and proteomic analyses. Statistical analyses, including the Wilcoxon rank-sum test and receiver operating characteristic curve analysis, were employed to evaluate the correlation between ARHGAP12 expression levels and clinical parameters, as well as drug sensitivity. It is evident that a more profound exploration of the molecular dynamics of HCC, especially those related to resistance against TKIs, is essential.
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Affiliation(s)
- Yu-Run Miao
- The First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
- Second Ward of General Surgery, Gansu Province People Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiao-Jun Yang
- Second Ward of General Surgery, Gansu Province People Hospital, Lanzhou 730000, Gansu Province, China
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Li K, Dai YJ, Zhang H, Zhang Z. YAP1 activates SLC2A1 transcription and augments the malignant behavior of colorectal cancer cells by activating the Wnt/β-catenin signaling pathway. Cell Div 2025; 20:8. [PMID: 40186232 PMCID: PMC11969700 DOI: 10.1186/s13008-025-00148-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 03/18/2025] [Indexed: 04/07/2025] Open
Abstract
OBJECTIVE This paper examined the role of solute carrier family 2 member 1 (SLC2A1) in colorectal cancer (CRC) progression, focusing on its expression levels, functional implications, and regulatory mechanisms involving Yes-associated protein 1 (YAP1) and the Wnt signaling pathway. METHODS GEO datasets (GSE14297, GSE18462, GSE40367) were analyzed to identify genes linked to metastasis in CRC, and TCGA-COAD system was used to analyze the expression pattern and prognostic values of SLC2A1 in CRC. Functional studies were conducted using CRC cell lines (Caco-2 and SW480). Cell viability, migration and invasion, and apoptosis were examined using EdU assays, Transwell assays, and flow cytometry. YAP1's regulatory role on SLC2A1 was investigated using ChIP-qPCR and luciferase reporter assays. The Wnt/β-catenin agonist SKL2001 was used for functional rescue experiments. RESULTS SLC2A1 was upregulated in CRC cells, and its upregulation was associated with tumor metastasis and unfavorable outcomes according to bioinformatics. Knockdown of SLC2A1 resulted in reduced cell viability, decreased migration, and increased apoptosis in Caco-2 and SW480 cells. Additionally, YAP1 was identified as a transcriptional activator of SLC2A1. Knockdown of YAP1 decreased SLC2A1 expression and reduced expression of Wnt target genes, thus suppressing malignant behavior of tumor cells. However, further overexpression of SLC2A1 restored cell viability and migration in YAP1-deficient cells. The YAP1- SLC2A1 axis activated the Wnt/β-catenin by reducing GSK3β activity. CONCLUSION SLC2A1 is critical in CRC progression, with YAP1 serving as a key regulator of its expression and function. The YAP1-SLC2A1-Wnt axis represents a potential therapeutic target for CRC, providing insights into metabolic adaptations that support tumor growth and metastasis.
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Affiliation(s)
- Kunpeng Li
- Zhongda Hospital of Southeast University, No 87 Dingjiaqiao, Nanjing, 210009, Jiangsu, PR China
| | - Ya-Jie Dai
- Department of General Surgery, Zhongda Hospital, Southeast University, Nanjing, 210009, Jiangsu, PR China
| | - Haifeng Zhang
- Department of General Surgery, Zhongda Hospital, Southeast University, Nanjing, 210009, Jiangsu, PR China
| | - Zhigang Zhang
- Department of General Surgery, Zhongda Hospital, Southeast University, Nanjing, 210009, Jiangsu, PR China.
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19
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Li Z, Zhang C, Huang G, Zhang Z, Wang Q, Liu X, Qin Y, Zhou H, Hou A, He J, Li L, Hu X, Ding X. Deletion of Tfap2a in hepatocytes and macrophages promotes the progression of hepatocellular carcinoma by regulating SREBP1/FASN/ACC pathway and anti-inflammatory effect of IL10. Cell Death Dis 2025; 16:245. [PMID: 40180937 PMCID: PMC11968862 DOI: 10.1038/s41419-025-07500-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 02/13/2025] [Accepted: 03/05/2025] [Indexed: 04/05/2025]
Abstract
The transcription factor AP-2α plays a crucial role in the control of tumor development and progression, and suppresses the proliferation and migration of hepatocellular carcinoma (HCC). However, the detailed function and mechanisms of AP-2α in the pathogenesis of HCC are still elusive. In the current study, we investigated the role of AP-2α regulation in liver injury-mediated HCC development. Downregulation of Tfap2a expression was found in the livers of DEN/CCl4-induced fibrosis and HCC mouse model. Hepatocyte (Alb-Cre), hepatic stellate cell (HSC) (Lrat-Cre) and macrophage (LysM-Cre) specific Tfap2a knockout mice were generated, respectively. Conditional knockout of Tfap2a was able to promote hepatic steatosis in Tfap2aΔHep and Tfap2aΔMΦ mice, but not in Tfap2aΔHSC mice fed with normal chow. Tfap2aΔHep and Tfap2aΔMΦ mice treated with DEN/CCl4 for 6 months increased tumor burden compared to Tfap2a flox controls. Tfap2a-deleted macrophages or hepatocytes could enhance lipid droplet (LD) accumulation in hepatocytes. Mechanistically, AP-2α binds to the promoter regions of SREBP1/ACC/FASN and inhibits hepatic lipid de novo synthesis. Deletion of Tfap2a in macrophages enhances polarization of M1 macrophages with increased iNOS expression but decreased CD206 expression, which resulted in increased pro-inflammatory cytokines and decreased anti-inflammatory factors, especially the hepatoprotective factor IL-10. The m6A modification writer WTAP could reduce the mRNA stability of AP-2α in a reader YTHDC1-dependent manner, whereas knockdown of WTAP or YTHDC1 enhances AP-2α expression and decreases lipid accumulation in HCC cells. Clinically, AP-2α expression negatively correlates with the expression of FASN, WTAP, YTHDC1 and the development of liver disease. Taken together, hepatocyte- or macrophage-specific deletion of Tfap2a promotes hepatic steatosis, fibrosis, and the development of HCC. These results suggest that AP-2α has been identified as a novel therapeutic target in fibrosis and inflammation-related HCC, exerting anti-lipogenesis, anti-inflammatory, and anti-tumor multi-roles.
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Affiliation(s)
- Zhiwei Li
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Chun Zhang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Guixiang Huang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Zixin Zhang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Qinghao Wang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Xiran Liu
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Yanling Qin
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Hao Zhou
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Anyi Hou
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Jun He
- Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, 410007, China
| | - Limin Li
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- College of Engineering and Design, Hunan Normal University, Changsha, 410081, China
| | - Xiang Hu
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, 410081, China
| | - Xiaofeng Ding
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China.
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
- Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, 410081, China.
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20
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Peng Z, Xu S, Wang H, Huang Y, Liu S, Jiao Z, Lin M, Zhu P, Chen Y, Shi Y, Wang Y, Li Y, Yuan W, Wu X, Jiang Z, Li F, Fan X. Identification of GDP as a small inhibitory molecule in HepG2 cells by non‑targeted metabolomics analysis. Oncol Lett 2025; 29:178. [PMID: 39990806 PMCID: PMC11843412 DOI: 10.3892/ol.2025.14924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 12/12/2024] [Indexed: 02/25/2025] Open
Abstract
Identifying the mechanism by which lipid metabolism regulates cancer may offer a novel approach for therapeutic intervention. It has previously been identified that a lipid metabolism-related factor, namely fatty acid hydroxylase domain containing 2 (FAXDC2), is downregulated in various types of cancer, and inhibits the proliferation and migration of liver cancer cells through a mechanism associated with ERK. The liver is important for lipid metabolism, and FAXDC2 is involved in the synthesis of cholesterol and sphingomyelin. However, the functional mechanism by which FAXDC2 influences liver cancer cells through metabolic processes and ERK signaling remains unclear. Therefore, the present study induced the overexpression of FAXDC2 in HepG2 liver cancer cells and performed a metabolomics analysis. This identified guanosine diphosphate (GDP) as a significantly altered metabolite. Using AlphaFold3, a robust interaction was predicted between FAXDC2 and GDP, which lead to the hypothesis that GDP may mediate the inhibitory effects of FAXDC2 on liver cancer cells by directly modulating the functional properties of the cells, thereby influencing their behavior and progression. Cell Counting Kit-8 assays were used to study the impact of elevated GDP concentrations on HepG2 cell growth. The results revealed a gradual reduction in the viability of HepG2 cells as the GDP concentration increased. In addition, western blotting showed that GDP treatment was accompanied by a significant downregulation of cyclin dependent kinase 4 and cyclin D1 expression levels, and Transwell experiments revealed that GDP treatment significantly decreased the invasion of HepG2 cells. Treatment with GDP also significantly inhibited the expression of ERK. In summary, the present study is the first to indicate that GDP is a metabolic small molecule with inhibitory activity in cancer cells, which has previously been overlooked in tumor metabolic reprogramming. The study findings offer new insights and strategies for the diagnosis and treatment of liver cancer, and potentially other types of cancer.
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Affiliation(s)
- Zhilin Peng
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Siting Xu
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Haocheng Wang
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Yanli Huang
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Siyuan Liu
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Zhongbei Jiao
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Mei Lin
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Ping Zhu
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangzhou, Guangdong 510100, P.R. China
| | - Yu Chen
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangzhou, Guangdong 510100, P.R. China
| | - Yan Shi
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangdong Provincial People's Hospital Affiliated to Southern Medical University, Guangzhou, Guangdong 510100, P.R. China
| | - Yuequn Wang
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Yongqing Li
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Wuzhou Yuan
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Xiushan Wu
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Zhigang Jiang
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Fang Li
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
| | - Xiongwei Fan
- The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China
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21
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Yang J, Zhang H, Yang L, Yi S, Zhang T. Investigating the Role of Scd1 in OSAHS-Induced Vascular Changes. J Biochem Mol Toxicol 2025; 39:e70221. [PMID: 40233246 DOI: 10.1002/jbt.70221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 01/16/2025] [Accepted: 03/03/2025] [Indexed: 04/17/2025]
Abstract
This study investigates the role of Stearoyl-CoA Desaturase-1 (Scd1) in vascular remodeling associated with Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) using multi-omics analysis. Transcriptomic and metabolomic datasets of OSAHS mouse models were analyzed to identify differentially expressed genes and metabolites, followed by functional enrichment analysis. Key genes were screened using weighted gene correlation network analysis (WGCNA) and machine learning, and a PPI network was constructed. An OSAHS mouse model was developed via intermittent hypoxia exposure. Human aortic smooth muscle cells (HASMCs) were subjected to hypoxia/reoxygenation cycles to simulate OSAHS in vitro. Blood pressure, plasma lipid profiles, histological changes in the thoracic aorta, and Scd1 protein expression were assessed. CCK-8 and Transwell assays evaluated HASMC proliferation and migration. Scd1 was identified as a critical factor in OSAHS-related vascular remodeling, with its expression significantly upregulated in vascular tissues of OSAHS mice. Metabolomic analysis revealed changes in fatty acid metabolism. Scd1 knockdown reduced blood pressure, lipid levels, aortic wall thickness, collagen deposition, elastic fiber accumulation, and mucin deposition in vivo. In vitro, hypoxia/reoxygenation cycles elevated Scd1 expression, while Scd1 knockdown inhibited HASMC proliferation and migration. Multi-omics analyses highlight Scd1 as a key regulator in OSAHS-associated vascular remodeling, driving pathological changes through its upregulation. These findings suggest Scd1 as a potential therapeutic target for managing OSAHS-related vascular pathologies.
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MESH Headings
- Stearoyl-CoA Desaturase/metabolism
- Stearoyl-CoA Desaturase/genetics
- Animals
- Mice
- Humans
- Vascular Remodeling
- Sleep Apnea, Obstructive/pathology
- Sleep Apnea, Obstructive/metabolism
- Sleep Apnea, Obstructive/genetics
- Sleep Apnea, Obstructive/enzymology
- Male
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Cell Proliferation
- Mice, Inbred C57BL
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/metabolism
- Disease Models, Animal
- Cell Movement
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Affiliation(s)
- Jing Yang
- Department of Respiratory and Critical Care Medicine, South China Hospital Affiliated to Shenzhen University, Shenzhen, China
| | - Hui Zhang
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Lulu Yang
- Department of General Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shen Yi
- Department of General Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ting Zhang
- Department II of Respiratory and Critical Care in Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
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22
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Eslam M, Fan JG, Yu ML, Wong VWS, Cua IH, Liu CJ, Tanwandee T, Gani R, Seto WK, Alam S, Young DY, Hamid S, Zheng MH, Kawaguchi T, Chan WK, Payawal D, Tan SS, Goh GBB, Strasser SI, Viet HD, Kao JH, Kim W, Kim SU, Keating SE, Yilmaz Y, Kamani L, Wang CC, Fouad Y, Abbas Z, Treeprasertsuk S, Thanapirom K, Al Mahtab M, Lkhagvaa U, Baatarkhuu O, Choudhury AK, Stedman CAM, Chowdhury A, Dokmeci AK, Wang FS, Lin HC, Huang JF, Howell J, Jia J, Alboraie M, Roberts SK, Yoneda M, Ghazinian H, Mirijanyan A, Nan Y, Lesmana CRA, Adams LA, Shiha G, Kumar M, Örmeci N, Wei L, Lau G, Omata M, Sarin SK, George J. The Asian Pacific association for the study of the liver clinical practice guidelines for the diagnosis and management of metabolic dysfunction-associated fatty liver disease. Hepatol Int 2025; 19:261-301. [PMID: 40016576 DOI: 10.1007/s12072-024-10774-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 12/28/2024] [Indexed: 03/01/2025]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over one-fourth of the global adult population and is the leading cause of liver disease worldwide. To address this, the Asian Pacific Association for the Study of the Liver (APASL) has created clinical practice guidelines focused on MAFLD. The guidelines cover various aspects of the disease, such as its epidemiology, diagnosis, screening, assessment, and treatment. The guidelines aim to advance clinical practice, knowledge, and research on MAFLD, particularly in special groups. The guidelines are designed to advance clinical practice, to provide evidence-based recommendations to assist healthcare stakeholders in decision-making and to improve patient care and disease awareness. The guidelines take into account the burden of clinical management for the healthcare sector.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, 2145, Australia.
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal MedicineCollege of Medicine and Center for Liquid Biopsy and Cohort ResearchFaculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of MedicineSchool of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, Kaohsiung Medical University, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
| | - Ian Homer Cua
- Institute of Digestive and Liver Diseases, St. Luke's Medical Center, Global City, Philippines
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal MedicineHepatitis Research CenterGraduate Institute of Clinical Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tawesak Tanwandee
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rino Gani
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Pangeran Diponegoro Road No. 71St, Central Jakarta, 10430, Indonesia
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Shahinul Alam
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Dan Yock Young
- Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
| | - Saeed Hamid
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Diana Payawal
- Department of Medicine, Cardinal Santos Medical Center, Mandaluyong, Philippines
| | - Soek-Siam Tan
- Department of Hepatology, Selayang Hospital, Batu Caves, Malaysia
| | - George Boon-Bee Goh
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
- Medicine Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
| | - Simone I Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Hang Dao Viet
- Internal Medicine Faculty, Hanoi Medical University, Hanoi, Vietnam
| | - Jia-Horng Kao
- Graduate Institute of Clinical MedicineDepartment of Internal MedicineHepatitis Research CenterDepartment of Medical Research, National Taiwan University College of Medicine, National Taiwan University, National Taiwan University Hospital, 1 Chang-Te Street, 10002, Taipei, Taiwan
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, 50-1, Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, Republic of Korea
| | - Shelley E Keating
- School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | | | - Chia-Chi Wang
- Buddhist Tzu Chi Medical Foundation and School of Medicine, Taipei Tzu Chi Hospital, Tzu Chi University, Taipei, Taiwan
| | - Yasser Fouad
- Department of Gastroenterology, Hepatology and Endemic Medicine, Faculty of Medicine, Minia University, Cairo, Egypt
| | - Zaigham Abbas
- Department of Hepatogastroenterology, Dr.Ziauddin University Hospital, Clifton, Karachi, Pakistan
| | | | | | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Undram Lkhagvaa
- Department of Health Policy, School of Public Health, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Oidov Baatarkhuu
- Department of Infectious Diseases, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Ashok Kumar Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - A Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Fu-Sheng Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, 100039, China
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Institute of Clinical Medicine, School of Medicine, Taipei Veterans General Hospital, National Yang-Ming Chiao Tung University, No. 201, Section 2, Shipai RdNo. 155, Section 2, Linong St, Beitou District, Taipei City, 112, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal MedicineCollege of Medicine and Center for Liquid Biopsy and Cohort ResearchFaculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jess Howell
- Burnet Institute, Melbourne, VIC, 3004, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Clayton, VIC, 3008, Australia
- Department of Medicine, The University of Melbourne, Parkville, VIC, 3050, Australia
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, VIC, 3165, Australia
| | - Jidong Jia
- Liver Research Center, Beijing Key Laboratory of Translational Medicine On Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Mohamed Alboraie
- Department of Internal Medicine, Al-Azhar University, Cairo, 11884, Egypt
| | - Stuart K Roberts
- Department of Gastroenterology and Hepatology, Central Clinical School, The Alfred, Monash University, Melbourne, Australia
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Hasmik Ghazinian
- Gastroenterology and Hepatology Department, Yerevan Medical Scientific Center, Yerevan, Armenia
| | - Aram Mirijanyan
- Gastroenterology and Hepatology Department, Yerevan Medical Scientific Center, Yerevan, Armenia
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China
| | | | - Leon A Adams
- Medical School, Faculty of Medicine and Health Sciences, The University of Western Australia, Nedlands, WA, Australia
| | - Gamal Shiha
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Necati Örmeci
- Department of Gastroenterohepatology, Istanbul Health and Technology University, Istanbul, Turkey
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - George Lau
- Humanity and Health Medical Group, Humanity and Health Clinical Trial Center, Hong Kong SAR, China
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Tokyo, Japan
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, 2145, Australia
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23
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Huang J, Xie H, Li J, Huang X, Cai Y, Yang R, Yang D, Bao W, Zhou Y, Li T, Lu Q. Histone lactylation drives liver cancer metastasis by facilitating NSF1-mediated ferroptosis resistance after microwave ablation. Redox Biol 2025; 81:103553. [PMID: 39970777 PMCID: PMC11876915 DOI: 10.1016/j.redox.2025.103553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 02/15/2025] [Indexed: 02/21/2025] Open
Abstract
Insufficient microwave ablation (IMWA) is linked to aggressive hepatocellular carcinoma (HCC) progression. An increase in lactate levels after sublethal heat stress (HS) has been confirmed in HCC. However, the role of lactate-related histone lactylation in the progression of HCC caused by sublethal HS remains unclear. Here, we found that the metastatic potential of HCC increased in a lactate-dependent manner after IMWA. Moreover, sublethal HS triggered an increase in H3K18la modification, as validated in a cell-derived xenograft mouse model and human HCC samples. By performing an integrated analysis of proteomic and transcriptomic profiles, we revealed that HCC cells exhibited increased intracellular iron ion homeostasis and developed resistance to platinum-based drugs after exposure to sublethal HS. We subsequently integrated proteomic and transcriptomic data with H3K18la-specific chromatin immunoprecipitation (ChIP) sequencing to identify candidate genes involved in sublethal heat treatment-induced HCC cell metastasis. Mechanically, an increase in H3K18la modification enhanced the transcriptional activity of NFS1 cysteine desulfurase (NFS1), a key player in iron‒sulfur cluster biosynthesis, thereby reducing the susceptibility of HCC to ferroptosis after IMWA. Knocking down NFS1 diminished the metastatic potential of sublethally heat-treated HCC cells. Additionally, NFS1 deficiency exhibited a synergistic effect with oxaliplatin, leading to the significant inhibition of the metastatic capability of HCC cells both in vitro and in vivo, regardless of sublethal HS treatment. In conclusion, our study revealed the oncogenic role of histone lactylation in HCC after IMVA. We also bridged histone lactylation with ferroptosis, providing novel therapeutic targets for HCC following microwave ablation, particularly when combined with oxaliplatin-based chemotherapy.
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Affiliation(s)
- Jiayan Huang
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Huijing Xie
- Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Ju Li
- Laboratory of Ultrasound Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Xiaotong Huang
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Yunshi Cai
- Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rui Yang
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Dongmei Yang
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Wuyongga Bao
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Yongjie Zhou
- Department of Liver Transplantation Center & Laboratory of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, 641400, China
| | - Tao Li
- Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China.
| | - Qiang Lu
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, 610041, China.
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24
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Yuan W, Lu G, Zhao Y, He X, Liao S, Wang Z, Lei X, Xie Z, Yang X, Tang S, Tang G, Deng X. Intranuclear TCA and mitochondrial overload: The nascent sprout of tumors metabolism. Cancer Lett 2025; 613:217527. [PMID: 39909232 DOI: 10.1016/j.canlet.2025.217527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/19/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
Abnormal glucose metabolism in tumors is a well-known form of metabolic reprogramming in tumor cells, the most representative of which, the Warburg effect, has been widely studied and discussed since its discovery. However, contradictions in a large number of studies and suboptimal efficacy of drugs targeting glycolysis have prompted us to further deepen our understanding of glucose metabolism in tumors. Here, we review recent studies on mitochondrial overload, nuclear localization of metabolizing enzymes, and intranuclear TCA (nTCA) in the context of the anomalies produced by inhibition of the Warburg effect. We provide plausible explanations for many of the contradictory points in the existing studies, including the causes of the Warburg effect. Furthermore, we provide a detailed prospective discussion of these studies in the context of these new findings, providing new ideas for the use of nTCA and mitochondrial overload in tumor therapy.
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Affiliation(s)
- Weixi Yuan
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Guozhong Lu
- 922nd Hospital of Hengyang, 421001, Hunan, China
| | - Yin Zhao
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiang He
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Senyi Liao
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Zhe Wang
- The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xiaoyong Lei
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Pharmacy, Xiangnan University, Chenzhou, 423000, China
| | - Zhizhong Xie
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiaoyan Yang
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Pharmacy, Xiangnan University, Chenzhou, 423000, China
| | - Shengsong Tang
- Hunan Province Key Laboratory for Antibody-based Drug and Intelligent Delivery Systems (2018TP1044), Hunan, 410007, China.
| | - Guotao Tang
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Xiangping Deng
- The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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Gu XY, Zhou ZJ, Yao H, Yang JL, Gu J, Mu R, Zhao LJ. The role of transketolase in the immunotherapy and prognosis of hepatocellular carcinoma: a multi-omics approach. Front Immunol 2025; 16:1529029. [PMID: 40230848 PMCID: PMC11994433 DOI: 10.3389/fimmu.2025.1529029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 03/12/2025] [Indexed: 04/16/2025] Open
Abstract
Objective To explore the role of transketolase (TKT) in the immunotherapy and prognosis of hepatocellular carcinoma (HCC). Materials and methods TKT expression across various cancers and its associations with tumor immunity and prognosis were analyzed using nomogram models. A multi-omics approach was employed, including bulk RNA-seq analysis, methylation profiling, single-cell analysis, and spatial transcriptomics. Experimental methods included RT-qPCR, siRNA transfection, luciferase reporter assay, and chromatin immunoprecipitation. Results TKT was significantly upregulated in multiple cancers and correlated with immune cell infiltration, particularly in HCC. Elevated TKT expression was associated with poor overall survival (OS) in HCC and was an independent prognostic factor (p < 0.05). Drug sensitivity analysis suggested that higher TKT expression was associated with reduced sensitivity to several chemotherapeutic agents, including sorafenib (p < 0.01). Furthermore, hypermethylation of the TKT promoter and low TKT expression were linked to improved OS in HCC (log-rank test p = 0.005). Single-cell analysis revealed that TKT was predominantly expressed in the monocyte/macrophage cluster associated with HCC, and pseudo-time series analysis highlighted TKT's role in cell differentiation within this cluster. Spatial transcriptomics confirmed the close association between TKT and macrophage distribution in HCC. Moreover, STAT3 was found to directly regulate TKT expression by binding to its promoter region. Conclusion Our findings suggest that TKT may play a role in tumor immunity and prognosis in HCC. Although these results provide insights into the potential involvement of TKT in immune cell infiltration and survival outcomes, further studies are required to fully elucidate its role in immunotherapy.
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Affiliation(s)
- Xuan-Yu Gu
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zheng-Jun Zhou
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Hua Yao
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jia-Li Yang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jin Gu
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Rui Mu
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Li-Jin Zhao
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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Wang YY, Yang WX, Cai JY, Wang FF, You CG. Comprehensive molecular characteristics of hepatocellular carcinoma based on multi-omics analysis. BMC Cancer 2025; 25:573. [PMID: 40159482 PMCID: PMC11956240 DOI: 10.1186/s12885-025-13952-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 03/17/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND The high heterogeneity of hepatocellular carcinoma (HCC) poses challenges for precision treatment strategies. This study aims to use multi-omics methodologies to better understand its pathogenesis and discover biomarkers. METHODS Quantitative proteomics was used to investigate hepatocellular carcinoma tissues (HCT) and their corresponding adjacent non-tumor tissues (DNT), obtained from six HCC patients. Untargeted metabolomics was applied to analyze the metabolic profiles of HCT and DNT of ten HCC patients. Statistical analyses, such as the Student's t-test, were performed to identify differentially expressed proteins (DEPs) and metabolites (DEMs) between the two groups. The functions and metabolic pathways involving DEPs and DEMs were annotated and enriched using the gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) databases. Bioinformatics methods were then utilized to analyze consistency between proteomics and metabolomics results, leading to identification of potential biomarkers along with key altered pathways associated with HCC. RESULTS This study identified 1556 DEPs between HCT and DNT samples. These DEPs were primarily enriched in crucial biological pathways such as amino acid degradation, fatty acid metabolism, and DNA replication. Subsequently, the analysis of metabolomics identified 500 DEMs that mainly participated in glycerophospholipid metabolism, the phospholipase D signaling pathway, and choline metabolism related to cancer. Integrated analysis of proteomics and metabolomics data unveiled significant dysfunctions in bile secretion, multiple amino acid and fatty acid metabolic pathways among HCC patients. Further investigation revealed that five proteins (PTP4A3, B4GALT5, GAB1, ME2, and PKM) along with seven metabolites (PI(6 keto-PGF1alpha/16:0), 13, 16, 19-docosatrienoic acid, PA(18:2(9Z, 12Z)/20:1(11Z)), Citric Acid, PG(20:3(6, 8, 11)-OH(5)/18:2(9Z, 12Z)), Spermidine, and N2-Acetylornithine) exhibited excellent diagnostic efficiency for HCC and could serve as its potential biomarkers. CONCLUSION Our integrated proteome and metabolome analysis revealed 10 key HCC-related pathways and proposed 12 potential biomarkers, which may enhance our understanding of HCC pathophysiology and be helpful in facilitating early diagnosis and treatment strategies.
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Affiliation(s)
- Ying-Ying Wang
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, 730030, China
| | - Wan-Xia Yang
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, 730030, China
| | - Jiang-Ying Cai
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, 730030, China
| | - Fang-Fang Wang
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, 730030, China
| | - Chong-Ge You
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, 730030, China.
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Zhao QY, Liu WJ, Wang JG, Li H, Lv JL, Wang Y, Wang C. Increasing cisplatin exposure promotes small-cell lung cancer transformation after a shift from glucose metabolism to fatty acid metabolism. J Cancer Res Clin Oncol 2025; 151:126. [PMID: 40155472 PMCID: PMC11953189 DOI: 10.1007/s00432-025-06164-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 03/10/2025] [Indexed: 04/01/2025]
Abstract
OBJECTIVES Lung cancer is a leading cause of global cancer mortality. Clinical observations reveal that histological transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is accompanied by mutations in TP53 and RB1. By applying gradually increasing cisplatin concentrations to mimic the escalating drug pressure within the tumor microenvironment, this study investigated the link between phenotypic transformation to SCLC in cisplatin-resistant human lung adenocarcinoma cells and alterations in cellular energy production pathways. MATERIALS AND METHODS We established two cisplatin-resistant NSCLC cell lines with varying resistance levels. RNAseq analyses identified TP53 and RB1 gene mutations. Comprehensive functional assays were performed to characterize A549/DDP1 μg/mL and A549/DDP3 μg/mL cells, focusing on proliferation and migratory capabilities. Cellular bioenergetics were assessed through glycolysis and oxidative phosphorylation analyses. Western blotting was employed to examine epithelial-mesenchymal transition (EMT), glucose metabolism, and lipid metabolism markers. Cell cycle distribution was analyzed by flow cytometry. Additionally, a xenograft mouse model was developed for in vivo validation. RESULTS TP53 and RB1 mutations were associated with cisplatin concentration-dependent phenotypic transformation, with A549/DDP cells acquiring a more aggressive SCLC-like phenotype (In the article we call the A549/DDPSCLC cells). Analysis of cell bioenergetics profiling and Western blot analyses revealed enhanced glucose metabolism in A549/DDP1 μg/mL cells, while A549/DDPSCLC cells exhibited predominant lipid metabolism. Compound3K and Etomoxir specifically inhibit the activity of PKM2 and CPT1A, respectively, with Etomoxir demonstrating substantially inhibited A549/DDPSCLC cells growth and more cell cycle arrest in the G0/G1 phase. Combinatorial of Compound3K and Etomoxir effectively induced cell death in A549/DDPSCLC phenotype cells in vitro. Etomoxir alone or combined with Compound3K significantly inhibited tumor growth in vivo, with enhanced efficacy in the combination group. CONCLUSIONS This study provides the first evidence of cisplatin concentration-dependent metabolic reprogramming during NSCLC-to-SCLC transformation. We identified a phenotypic transition from NSCLC to SCLC accompanied by a metabolic shift from glucose to fatty acid metabolism, offering new insights into therapeutic strategies for treatmentresistant lung cancer.
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Affiliation(s)
- Qiu-Yu Zhao
- College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, Liaoning, People's Republic of China
- Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, Liaoning, People's Republic of China
| | - Wen-Jun Liu
- Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, Liaoning, People's Republic of China
- Teaching and Experimental Center, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, Liaoning, People's Republic of China
| | - Jian-Guang Wang
- College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, Liaoning, People's Republic of China
| | - He Li
- College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, Liaoning, People's Republic of China
| | - Jia-Lu Lv
- College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, Liaoning, People's Republic of China
| | - Yumeng Wang
- School of Biomedical Engineering, Shanghai Tech University, Shanghai, 201210, China
| | - Chun Wang
- College of Integrated Chinese and Western Medical, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, Liaoning, People's Republic of China.
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Xi D, Yang Y, Guo J, Wang M, Yan X, Li C. Single-cell sequencing and spatial transcriptomics reveal the evolution of glucose metabolism in hepatocellular carcinoma and identify G6PD as a potential therapeutic target. Front Oncol 2025; 15:1553722. [PMID: 40201344 PMCID: PMC11975570 DOI: 10.3389/fonc.2025.1553722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Accepted: 03/04/2025] [Indexed: 04/10/2025] Open
Abstract
Background Glucose metabolism reprogramming provides significant insights into the development and progression of malignant tumors. This study aims to explore the temporal-spatial evolution of the glucose metabolism in HCC using single-cell sequencing and spatial transcriptomics (ST), and validates G6PD as a potential therapeutic target for HCC. Methods We collected single-cell sequencing data from 7 HCC and adjacent non-cancerous tissues from the GSE149614 database, and ST data from 4 HCC tissues from the HRA000437 database. Pseudotime analysis was performed on the single-cell data, while ST data was used to analyze spatial metabolic activity. High-throughput sequencing and experiments, including wound healing, CCK-8, and transwell assays, were conducted to validate the role and regulatory mechanisms of G6PD in HCC. Results Our study identified a progressive upregulation of PPP-related genes during tumorigenesis. ST analysis revealed elevated PPP metabolic scores in the central and intermediate tumor regions compared to the peripheral zones. High-throughput sequencing and experimental validation further suggested that G6PD-mediated regulation of HCC cell proliferation, migration, and invasion is likely associated with glutathione metabolism and ROS production. Finally, Cox regression analysis cofirmed G6PD as an independent prognostic factor for overall survival in HCC patients. Conclusion Our study provides novel insights into the changes in glucose metabolism in HCC from both temporal and spatial perspectives. We experimentally demonstrated that G6PD regulates proliferation, migration, and invasion in HCC and propose G6PD as a prognostic marker and therapeutic metabolic target for the HCC.
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Affiliation(s)
- Deyang Xi
- Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yinshuang Yang
- Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jiayi Guo
- Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Mengjiao Wang
- Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xuebing Yan
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Chunyang Li
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
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He S, Lv Y, Qiu J, Cui S, Gao Z, Peng L. Ta 4C 3 MXene Slows Progression of Fatty Liver Disease through Its Anti-Inflammatory and ROS-Scavenging Effects. ACS APPLIED MATERIALS & INTERFACES 2025; 17:17217-17229. [PMID: 40051029 DOI: 10.1021/acsami.4c20945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/21/2025]
Abstract
Treating metabolic dysfunction-associated fatty liver disease (MAFLD) and reducing the occurrence of MAFLD-associated liver cancer remain challenging. Two-dimensional (2D) tantalum carbide (Ta4C3) MXene nanozymes (MXenzymes) exhibit antioxidant and anti-inflammatory activities and have thus attracted considerable attention in the fields of oncology and engineering. However, the potential mechanism of action and bioactive properties of Ta4C3 in MAFLD remain uncertain. In our study, Ta4C3 not only inhibited lipid accumulation and disrupted lipid metabolism in hepatocytes but also reduced cell death caused by fatty acids by decreasing intracellular reactive oxygen species (ROS) levels, which significantly promoted the polarization of M1 macrophages to M2 macrophages by alleviating oxidative stress and further suppressing inflammatory factor expression. In mice fed a methionine-choline-deficient (MCD) diet, Ta4C3 reduced lipid accumulation, the infiltration of inflammatory cells, and liver cell apoptosis by modulating the cellular microenvironment through its anti-inflammatory and antioxidant properties. Therefore, Ta4C3 can be used as a multifunctional bioactive material to alleviate hepatic steatosis and inflammation in individuals with MAFLD/metabolic dysfunction-associated steatohepatitis (MASH) because of its robust antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Shuying He
- Department of Gastroenterology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Yuerong Lv
- Department of Gastroenterology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Jingnan Qiu
- Department of Gastroenterology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Shudan Cui
- Department of Gastroenterology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Zixian Gao
- Department of Gastroenterology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Liang Peng
- Department of Gastroenterology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China
- Department of Medicine, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China
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Liu W, Hu K, Fu Y, Zhou T, Zhong Q, Wang W, Gui Y, Zhang P, Yao D, Yang X, Zhu W, Liu Z, Luo D, Xiao Y. Identification of methionine metabolism related prognostic model and tumor suppressive functions of BHMT in hepatocellular carcinoma. Sci Rep 2025; 15:9250. [PMID: 40102459 PMCID: PMC11920202 DOI: 10.1038/s41598-025-93650-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 03/07/2025] [Indexed: 03/20/2025] Open
Abstract
Given the resistance to conventional treatments and limitations of immune checkpoint blockade therapy in hepatocellular carcinoma (HCC), it is imperative to explore novel prognostic models and biomarkers. The dependence of cancer cell on exogenous methionine, known as Hoffman effect, is a hallmark of HCC, with numerous studies reporting a strong correlation between methionine metabolism and tumor development. Betaine-homocysteine S-methyltransferase (BHMT), a critical component of methionine metabolism pathway, has polymorphisms linking to poor prognosis in multiple cancers. Nevertheless, there is little literature regarding the relationship between methionine metabolism and incidence, mortality of HCC, as well as the function of BHMT in HCC progression. In this study, by analyzing multiple datasets, we constructed a methionine metabolism-related prognostic model and thoroughly investigated the influence of BHMT on the prognosis of HCC. Bioinformatics analysis revealed a marked decrease in BHMT expression in HCC, which was linked to adverse clinical outcomes. CIBERSORT results suggest that BHMT promotes infiltration of M1 macrophages. Our results suggest its potential as an ideal prognostic biomarker for anti PD-L1 immunotherapy. In summary, this study innovatively provides first methionine metabolism-related prognostic model and unveils the tumor suppressive function of BHMT in HCC, providing potential mechanism by which BHMT exert its function.
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Affiliation(s)
- Wenli Liu
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Kaiheng Hu
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yaqing Fu
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Tianmin Zhou
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Qingmei Zhong
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Wu Wang
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Yang Gui
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Ping Zhang
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Di Yao
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China
| | - Xiaohong Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Weifeng Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Zhuoqi Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
| | - Daya Luo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
| | - Yingqun Xiao
- Department of Pathology, Infectious Diseases Hospital of Nanchang University, Nanchang, 330001, Jiangxi, China.
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Wang M, Huang X, Zhang D, Liu Y, Liu P. The role of fructose-1,6-bisphosphatase 1 on regulating the cancer progression and drug resistance. Discov Oncol 2025; 16:346. [PMID: 40100307 PMCID: PMC11920503 DOI: 10.1007/s12672-025-02112-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 03/10/2025] [Indexed: 03/20/2025] Open
Abstract
Fructose-1,6-bisphosphatase 1 (FBP1) is the enzyme that limits the process of gluconeogenesis as it facilitates the hydrolysis of fructose-1,6-bisphosphate(F-1,6-BP) to produce fructose-6-phosphate(F6P) and inorganic phosphate. Gluconeogenesis is the production of glucose from small carbohydrate substrates. The gluconeogenic process is typically suppressed in cancer because it inhibits glycolysis. Apart from its involvement in cellular glucose metabolism, FBP1 also plays a role in gene transcription, mRNA translation and stability regulation, and the immune microenvironment of tumors. Because of its multifaceted functions, the mechanisms by which FBP1 is involved in tumor development are complex. Moreover, FBP1 deficiency is associated with radiation and chemotherapy resistance and poor prognosis in cancer patients. Restoration of FBP1 expression in cancer cells is expected to hold promise for cancer therapy. However, up to now few reviews have systematically summarized the important functional mechanisms of FBP1 in tumorigenesis and the small molecule compounds that restore FBP1 expression. Therefore, this article addresses the question "How does FBP1 contribute to cancer progression, and can targeting FBP1 be a potential therapeutic approach?" by summarizing the effects of FBP1 on cancer development and progression as well as its mediated drug resistance and the future clinical applications of potential small molecule modulators targeting FBP1.
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Affiliation(s)
- Mengmeng Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Xiaoju Huang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Dan Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Yisan Liu
- Department of Urology, People's Hospital of Cili, Cili, 427200, Hunan, China.
| | - Pian Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China.
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Chen J, Wei C, Huang W, Huang T, Zhou L, Xu Y, Qin Y, Lin Q, Liu F, Pan X, Tang Z, Yang W, Fang M. Clonorchis sinensis-infected hepatocellular carcinoma exhibits distinct tumor microenvironment and molecular features. Front Immunol 2025; 16:1526699. [PMID: 40165955 PMCID: PMC11955701 DOI: 10.3389/fimmu.2025.1526699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/26/2025] [Indexed: 04/02/2025] Open
Abstract
Objectives Clonorchis sinensis (Cs)-infected hepatocellular carcinoma (HCC) patients have a poorer prognosis than non-Cs-infected HCCs. However, the molecular mechanisms of Cs-infected HCC remain unclear. To address this, this study aims to uncover the tumor microenvironment and molecular features that may contribute to these poor outcomes. Methods The research involved bulk RNA sequencing of paired tumor and adjacent tissue samples from 10 Cs + HCC and 10 Cs - HCC patients. Differentially expressed genes were identified, followed by enrichment analyses to reveal functional changes. Survival analysis of the top 10 up- and down-regulated genes in Cs + HCC tumors was performed using TCGA database. Additionally, clinical data from 1,461 HCC patients were retrospectively analyzed to assess the impact of Cs infection on microvascular invasion and metastasis rates. In vitro assays were also conducted using Cs excretory/secretory products (CsESPs) to examine their effect on HCC cells and HUVECs. Results We identified 785 up-regulated and 675 down-regulated genes in Cs + HCC tumors compared to Cs - HCC tumors, enriched in pathways related to extracellular matrix remodeling and immunosuppression. Survival analysis revealed that the top 10 up-regulated genes are associated with HCC poor prognosis. Clinical data from 1,461 HCC patients showed Cs infection increased microvascular invasion and metastasis rates. In vitro, CsESPs products enhanced migration and invasion in HCC cells and promoted tube formation in human umbilical vein endothelial cells. Conclusions This study provides novel insights into the molecular landscape of Cs-infected HCC and underscores the Cs infection's role in enhancing tumor migration, invasion and angiogenesis. The findings contribute to the understanding of parasitic infections in cancer progression and suggest potential prognostic markers for Cs + HCC.
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Affiliation(s)
- Junxian Chen
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Caibiao Wei
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Wencheng Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Taijun Huang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Lingling Zhou
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yulong Xu
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yuling Qin
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Qiumei Lin
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Fengfei Liu
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xiaolan Pan
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Zeli Tang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Weilong Yang
- Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
- Institute of Advanced Biotechnology and School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Min Fang
- Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China
- Engineering Research Center for Tissue and Organ Injury and Repair Medicine, Guangxi Medical University Cancer Hospital, Nanning, China
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Zhang B, Zheng J, Zheng S. Cirsiliol suppresses malignant progression of hepatocellular carcinoma via regulation of glutamine metabolism. Am J Transl Res 2025; 17:2145-2153. [PMID: 40226041 PMCID: PMC11982850 DOI: 10.62347/aoty4308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 12/06/2024] [Indexed: 04/15/2025]
Abstract
BACKGROUND To investigate the therapeutic potential of cirsiliol in hepatocellular carcinoma (HCC), focusing on its impact on glutamine metabolism. METHODS HCC cell lines HCCLM3 and Huh7 were treated with cirsiliol, and cell viability and proliferation were assessed using CCK-8 assay. Intracellular concentrations of glutamine, α-ketoglutaric acid (α-KG), and adenosine triphosphate (ATP) were measured to evaluate glutamine metabolism. A xenograft tumor model was employed to examine the in vivo effects of cirsiliol. Additionally, network pharmacological analysis was used to identify potential targets of cirsiliol in HCC. Western blotting was conducted to analyze the modulation of the PI3K/AKT signaling pathway by cirsiliol. RESULTS Cirsiliol significantly inhibited HCC cell growth both in vitro and in vivo while reducing levels of glutamine, α-KG, and ATP, indicating suppression of glutamine metabolism. Activation of the PI3K signaling pathway reversed the inhibitory effects of cirsiliol on HCC cell growth and metabolism. CONCLUSION Cirsiliol suppresses glutamine metabolism and inhibits the growth of HCC cells by modulating the PI3K/AKT signaling pathway.
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Affiliation(s)
- Bin Zhang
- Hepatopancreatobiliary Surgery Department, The First Affiliated Hospital of Ningbo University No. 59, Liuting Street, Haishu District, Ningbo 315000, Zhejiang, China
| | - Jianbo Zheng
- Hepatopancreatobiliary Surgery Department, The First Affiliated Hospital of Ningbo University No. 59, Liuting Street, Haishu District, Ningbo 315000, Zhejiang, China
| | - Siming Zheng
- Hepatopancreatobiliary Surgery Department, The First Affiliated Hospital of Ningbo University No. 59, Liuting Street, Haishu District, Ningbo 315000, Zhejiang, China
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Wang C, Zhou J, Jia P, Yang Y, Song R, Zheng X, Zhang H, Li Y. Joint proteomic and metabolomic analysis reveals renal metabolic remodeling of chronic heart failure mice. J Pharm Biomed Anal 2025; 255:116641. [PMID: 39731929 DOI: 10.1016/j.jpba.2024.116641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/01/2024] [Accepted: 12/15/2024] [Indexed: 12/30/2024]
Abstract
Pharmacologic intervention in chronic heart failure (HF) with renal insufficiency is one of the clinical challenges due to the fact that the mechanisms of cardio-renal interactions in chronic heart failure (CHF) progressing have not been fully revealed. In this paper, C57BL/6 mice were applied thoracic aortic narrowing surgery to establish pressure overload CHF model. Cardiac function, serum markers, renal pathologic changes and kidney metabolism were analyzed at 4th, 8th, 12th, and 16th week after surgery respectively to evaluate the heart-Kidney pathologic overlap. Kidney proteomic analysis was performed at 16th week after operation. As a result, renal hypofiltration and exacerbation of pathological damage was observed accompanying cardiac function deterioration after 12th week. 66 differentially expressed proteins and 13 differential metabolites were found to be involved in the cardio-renal pathological overlap. Joint proteomic and metabolomic analysis revealed that signal pathways like Phosphatidylinositol signaling system, Glucagon signaling pathway, the Glyoxylate and dicarboxylate metabolism; DEPs of Pten, Mtmr4, PLC and CPT1, differential metabolites like aspartic acid and isocitrate deserve further investigation.
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Affiliation(s)
- Chunliu Wang
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, Shaanxi, China; Key Laboratory of TCM Drug Delivery, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, Shaanxi, China
| | - Jie Zhou
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Pu Jia
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an, Shaanxi, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an, Shaanxi, China
| | - Ruixue Song
- Xi'an Research Institute of Chinese Lacquer, Xi'an, Shaanxi, China
| | - Xiaohui Zheng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an, Shaanxi, China
| | - Hong Zhang
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, Shaanxi, China; Key Laboratory of TCM Drug Delivery, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, Shaanxi, China.
| | - Ye Li
- Institute of Traditional Chinese Medicine, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, Shaanxi, China; Key Laboratory of TCM Drug Delivery, Shaanxi Academy of Traditional Chinese Medicine, Xi'an, Shaanxi, China.
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Wang LL, Zhang FC, Xu HX, Deng DD, Ren BJ, Tan Q, Liu YX, Zhao WH, Lu JL. Advances in imaging techniques for tumor microenvironment evaluation in hepatocellular carcinoma. World J Gastroenterol 2025; 31:103454. [PMID: 40093677 PMCID: PMC11886532 DOI: 10.3748/wjg.v31.i10.103454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/31/2024] [Accepted: 02/11/2025] [Indexed: 02/26/2025] Open
Abstract
The tumor microenvironment (TME) plays a critical role in the development and treatment of liver cancer, which ranks sixth in incidence and third in mortality worldwide, according to the "Global Cancer Statistics 2022". Hepatocellular carcinoma (HCC), the most common form of liver cancer, is heavily influenced by the TME, which affects tumor growth, invasion, metastasis, and the response to various treatments. Despite advancements in surgery, liver transplantation, targeted therapies, and immunotherapy, the complexity of the TME often limits treatment efficacy, especially in advanced-stage HCC cases. The TME consists of a dynamic interaction between tumor cells, immune cells, fibroblasts, blood vessels, and signaling molecules, all of which contribute to cancer progression and therapy resistance. Assessing the HCC TME is essential for designing effective, personalized treatments and improving patient outcomes. Recent research highlights the value of imaging technologies as non-invasive tools to evaluate the TME, offering new possibilities for more targeted therapies and better prognosis monitoring in HCC patients.
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Affiliation(s)
- Li-Li Wang
- Department of Radiology, The First Hospital of Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Fa-Chang Zhang
- First Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Han-Xin Xu
- First Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Dian-Dian Deng
- First Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Bing-Jie Ren
- First Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Qi Tan
- First Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Ya-Xin Liu
- First Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Wen-Hui Zhao
- First Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Jia-Le Lu
- First Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou 730030, Gansu Province, China
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Li S, Wang X, Xiao J, Yi J. SLC7A11, a disulfidptosis-related gene, correlates with multi-omics prognostic analysis in hepatocellular carcinoma. Eur J Med Res 2025; 30:161. [PMID: 40069889 PMCID: PMC11900568 DOI: 10.1186/s40001-025-02411-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND This study sought to establish a risk score signature based on disulfidptosis-related genes (DRGs) to predict the prognosis of hepatocellular carcinoma (HCC) patients. METHODS The expression data of DRGs from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) was analyzed to develop and validate a DRG prognostic signature (DRGPS). In vitro, experiments were conducted to explore DRG expressions and roles in HCC tissues and cell lines. HCC tissue microarrays were employed to analyze SLC7A11 expression and its association with clinicopathological characteristics. RESULTS The DRGPS consisted of 5 DRGs (SLC7A11, MATN3, CLEC3B, CCNJL, and PON1). The survival rate of HCC patients in high-risk group was significantly lower than that in low-risk group. The DRGPS was also associated with the modulation of tumor microenvironment (TME), tumor mutation burden (TMB), stemness and chemosensitivity. Furthermore, pan-cancer analysis suggested that the DRGPS risk score was associated with immune infiltration and stemness in multiple cancers. Moreover, our DRGPS had potential for predicting treatment efficacy in HCC patients. Finally, we confirmed that downregulation of SLC7A11, a DRG, inhibited the proliferation and migration of HCC cells, while its high expression correlated with advanced TNM clinical stage and larger tumor size. CONCLUSIONS This study systematically describes a novel DRGPS constructed for predicting HCC prognosis, providing a new approach to risk stratification and treatment options. It also investigates the expression and function of SLC7A11, contributing to further exploration of the molecular mechanism underlying disulfidptosis in HCC, as well as its prognostic and therapeutic implications.
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Affiliation(s)
- Shizhe Li
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, China
| | - Xiaotong Wang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, China
| | - Junbo Xiao
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, China.
| | - Jun Yi
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, China.
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Li S, Lu Z, Jiang W, Xu Y, Chen R, Wang J, Jiao B, Lu X. Chaetocin, a Natural Inhibitor of Transketolase, Suppresses the Non-Oxidative Pentose Phosphate Pathway and Inhibits the Growth of Drug-Resistant Non-Small Cell Lung Cancer. Antioxidants (Basel) 2025; 14:330. [PMID: 40227333 PMCID: PMC11939327 DOI: 10.3390/antiox14030330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/16/2025] [Accepted: 03/09/2025] [Indexed: 04/15/2025] Open
Abstract
Worldwide, lung cancer is the most common cause of cancer-related death, which is made worse by the development of drug resistance during treatment. It is urgent to develop new therapeutic methods and small molecule drugs for tumor resistance. Chaetocin, extracted from Chaetomium minutum, is a natural compound with good antitumor activity. However, there are few studies on its tumor resistance. In this paper, firstly, chaetotocin significantly inhibited the viability and migration of cisplatin-resistant non-small cell lung cancer (NSCLC) cells and inhibited the xenograft growth of nude mice. Chaetocin at 4 mg/kg significantly inhibited A549/DDP xenograft growth with an inhibition rate of 70.43%. Subsequently, the underlying mechanism behind the actions of chaetocin was explored. It was discovered that chaetocin can inhibit transketolase (TKT), thereby inhibiting the growth of NSCLC cells and inducing cell death. Compared with cisplatin-sensitive cells, a lower concentration of chaetocin can inhibit cisplatin-resistance cell viability and migration. Mechanistically, TKT was identified as a potential target for chaetocin. The KD value of the interaction between chaetocin and TKT was 63.2 μM. An amount of 0.2 μM chaetocin may suppress the enzyme activity and expression level of TKT. We found the TKT expression is higher in cisplatin-resistant cells, which further explains why these cells were more vulnerable to chaetocin in terms of cell phenotype. Additionally, the muti-omics analysis and RNA interference suggested that chaetocin can inhibit the PI3K/Akt signaling pathway through TKT. In conclusion, chaetocin could directly bind to TKT, inhibiting its enzyme activity and expression, which interfered with intracellular metabolism and oxidation-reduction balance, and then regulated the PI3K/Akt signaling pathway to inhibit the growth of NSCLC and induce apoptosis.
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Affiliation(s)
- Song Li
- Department of Biochemistry and Molecular Biology, Naval Medical University, Shanghai 200433, China; (S.L.); (W.J.); (Y.X.); (R.C.); (J.W.)
| | - Zhanying Lu
- Experimental Training Center of Basic Medical Science, Naval Medical University, Shanghai 200433, China;
| | - Wenli Jiang
- Department of Biochemistry and Molecular Biology, Naval Medical University, Shanghai 200433, China; (S.L.); (W.J.); (Y.X.); (R.C.); (J.W.)
| | - Yao Xu
- Department of Biochemistry and Molecular Biology, Naval Medical University, Shanghai 200433, China; (S.L.); (W.J.); (Y.X.); (R.C.); (J.W.)
| | - Ran Chen
- Department of Biochemistry and Molecular Biology, Naval Medical University, Shanghai 200433, China; (S.L.); (W.J.); (Y.X.); (R.C.); (J.W.)
| | - Jie Wang
- Department of Biochemistry and Molecular Biology, Naval Medical University, Shanghai 200433, China; (S.L.); (W.J.); (Y.X.); (R.C.); (J.W.)
| | - Binghua Jiao
- Department of Biochemistry and Molecular Biology, Naval Medical University, Shanghai 200433, China; (S.L.); (W.J.); (Y.X.); (R.C.); (J.W.)
| | - Xiaoling Lu
- Department of Biochemistry and Molecular Biology, Naval Medical University, Shanghai 200433, China; (S.L.); (W.J.); (Y.X.); (R.C.); (J.W.)
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Xie X, Liu W, Yuan Z, Chen H, Mao W. Bridging epigenomics and tumor immunometabolism: molecular mechanisms and therapeutic implications. Mol Cancer 2025; 24:71. [PMID: 40057791 PMCID: PMC11889836 DOI: 10.1186/s12943-025-02269-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/11/2025] [Indexed: 04/02/2025] Open
Abstract
Epigenomic modifications-such as DNA methylation, histone acetylation, and histone methylation-and their implications in tumorigenesis, progression, and treatment have emerged as a pivotal field in cancer research. Tumors undergo metabolic reprogramming to sustain proliferation and metastasis in nutrient-deficient conditions, while suppressing anti-tumor immunity in the tumor microenvironment (TME). Concurrently, immune cells within the immunosuppressive TME undergo metabolic adaptations, leading to alterations in their immune function. The complicated interplay between metabolites and epigenomic modulation has spotlighted the significance of epigenomic regulation in tumor immunometabolism. In this review, characteristics of the epigenomic modification associated with tumors are systematically summarized alongside with their regulatory roles in tumor metabolic reprogramming and immunometabolism. Classical and emerging approaches are delineated to broaden the boundaries of research on the crosstalk research on the crosstalk between tumor immunometabolism and epigenomics. Furthermore, we discuss potential therapeutic strategies that target tumor immunometabolism to modulate epigenomic modifications, highlighting the burgeoning synergy between metabolic therapies and immunotherapy as a promising avenue for cancer treatment.
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Affiliation(s)
- Xiaowen Xie
- Department of Thoracic Surgery, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, China
| | - Weici Liu
- Department of Thoracic Surgery, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, China
- Center of Clinical Research, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Zhiyuan Yuan
- Institute of Science and Technology for Brain-Inspired Intelligence; MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence; MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, China.
| | - Hanqing Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, China.
| | - Wenjun Mao
- Department of Thoracic Surgery, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, China.
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Liu P, Huang F, Lin P, Liu J, Zhou P, Wang J, Sun H, Xing F, Ma H. Histidine metabolism drives liver cancer progression via immune microenvironment modulation through metabolic reprogramming. J Transl Med 2025; 23:262. [PMID: 40038727 PMCID: PMC11877819 DOI: 10.1186/s12967-025-06267-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 02/14/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Histidine metabolism is crucial in role in tumor biology, contributing to tumor progression, immune regulation, and metabolic reprogramming. In hepatocellular carcinoma (HCC), dysregulated histidine metabolism may promote tumor growth and immune evasion, although the specific mechanisms remain poorly understood. METHODS Using single-cell RNA sequencing, the expression patterns of histidine metabolism-related genes were evaluated across different cell types in HCC samples. In vivo and in vitro experiments were conducted to validate how histidine treatment affects macrophage and T-cell function. Furthermore, the TCGA database was utilized to construct a prognostic model to identify the key gene BUD23 and to examine its correlation with metabolism and immune infiltration. RESULTS The proportion of parenchymal cells exhibiting high histidine metabolism was significantly increased, accompanied by a general reduction in immune and stromal cell infiltration. Notably, macrophages and T cells demonstrated impaired antitumor functions. In the high histidine metabolism group, multiple critical cell communication pathways (e.g., MIF, CLEC, MHC II) were downregulated, macrophages shifted toward immunosuppressive subpopulations, T cells exhibited an exhaustion phenotype, and CD8 + T-cell activation was diminished. Further in vivo and in vitro co-culture experiments confirmed that elevated histidine concentrations promoted M2 polarization in macrophages and weakened T-cell cytotoxicity, accelerating tumor proliferation. According to TCGA analyses, BUD23 was upregulated in the high histidine metabolism group and significantly negatively correlated with patient survival and immune cell infiltration. Silencing BUD23 boosted immune cell activation and cytotoxic effects, effectively reversing the immunosuppressive microenvironment. A multivariable Cox regression-based prognostic model indicated unfavorable outcomes in patients with high histidine metabolism. CONCLUSION Histidine metabolism drives tumor cell metabolic reprogramming and reshapes the tumor immune microenvironment through intercellular communication, thereby promoting tumor progression. BUD23 shows promise as a biomarker for prognosis and immune response prediction in liver cancer. This study provides new therapeutic targets and theoretical support for liver cancer treatment by targeting histidine metabolism.
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Affiliation(s)
- Pengcheng Liu
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University School of Medicine, Guangzhou, 510006, China
| | - Fuxin Huang
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Peixu Lin
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University School of Medicine, Guangzhou, 510006, China
| | - Jiayao Liu
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Pincheng Zhou
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Jie Wang
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510006, China
| | - Huanhuan Sun
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University School of Medicine, Guangzhou, 510006, China.
| | - Fan Xing
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University School of Medicine, Guangzhou, 510006, China.
| | - Haiqing Ma
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University School of Medicine, Guangzhou, 510006, China.
- Department of Oncology, Heyuan Hospital of Guangdong Provincial People's Hospital, Heyuan People's Hospital, Heyuan, 517000, China.
- School of Medicine, South China University of Technology, Guangzhou, 510006, China.
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510006, China.
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Karim M, Prey J, Willer F, Leiner H, Yasser M, Dombrowski F, Ribback S. Hepatic Deletion of Carbohydrate Response Element Binding Protein Impairs Hepatocarcinogenesis in a High-Fat Diet-Induced Mouse Model. Int J Mol Sci 2025; 26:2246. [PMID: 40076869 PMCID: PMC11900174 DOI: 10.3390/ijms26052246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/06/2025] [Accepted: 02/07/2025] [Indexed: 03/14/2025] Open
Abstract
The transcription factor carbohydrate response element binding protein (ChREBP) has emerged as a crucial regulator of hepatic glucose and lipid metabolism. The increased ChREBP activity involves the pro-oncogenic PI3K/AKT/mTOR signaling pathway that induces aberrant lipogenesis, thereby promoting hepatocellular carcinomas (HCC). However, the molecular pathogenesis of ChREBP-related hepatocarcinogenesis remains unexplored in the high-fat diet (HFD)-induced mouse model. Male C57BL/6J (WT) and liver-specific (L)-ChREBP-KO mice were maintained on either a HFD or a control diet for 12, 24, and 48 weeks, starting at the age of 4 weeks. At the end of the feeding period, mice were perfused, and liver tissues were formalin-fixed, paraffin-embedded, sectioned, and stained for histological and immunohistochemical analysis. Biochemical and gene expression analysis were conducted using serum and frozen liver tissue. Mice fed with HFD showed a significant increase (p < 0.05) in body weight from 8 weeks onwards compared to the control. WT and L-ChREBP-KO mice also demonstrated a significant increase (p < 0.05) in liver-to-body weight ratio in the 48-week HFD group. HFD mice exhibited a gradual rise in hepatic lipid accumulation over time, with 24-week mice showing a 20-30% increase in fat content, which further advanced to 80-100% fat accumulation at 48 weeks. Both dietary source and the increased expression of lipogenic pathways at transcriptional and protein levels induced steatosis and steatohepatitis in the HFD group. Moreover, WT mice on a HFD exhibited markedly higher inflammation compared to the L-ChREBP-KO mice. The enhanced lipogenesis, glycolysis, persistent inflammation, and activation of the AKT/mTOR pathway collectively resulted in significant metabolic disturbances, thereby promoting HCC development and progression in WT mice. In contrast, hepatic loss of ChREBP resulted in reduced hepatocyte proliferation in the HFD group, which significantly contributed to the impaired hepatocarcinogenesis and a reduced HCC occurrence in the L-ChREBP-KO mice. Our present study implicates that prolonged HFD feeding contributes to NAFLD/NASH, which in turn progresses to HCC development in WT mice. Collectively, hepatic ChREBP deletion ameliorates hepatic inflammation and metabolic alterations, thereby impairing NASH-driven hepatocarcinogenesis.
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Affiliation(s)
| | | | | | | | | | | | - Silvia Ribback
- Institute of Pathology, University Medicine Greifswald, Friedrich-Loeffler-Str. 23e, 17475 Greifswald, Germany; (M.K.); (J.P.); (F.W.); (M.Y.); (F.D.)
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Zuo H, Liu X, Wang Y, Ding H, Wan W, Zheng S, Hou S, Hu K. SREBF1 facilitates pathological retinal neovascularization by reprogramming the fatty acid metabolism of endothelial cells. Exp Eye Res 2025; 252:110239. [PMID: 39800283 DOI: 10.1016/j.exer.2025.110239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/03/2024] [Accepted: 01/09/2025] [Indexed: 01/31/2025]
Abstract
Retinopathy of prematurity (ROP) is a proliferative retinal vascular disorder that critically affects the visual development of premature infants, potentially leading to irreversible vision loss or even blindness. Despite its significance, the underlying mechanisms of this disease remain insufficiently understood. In this study, we utilized the oxygen-induced retinopathy (OIR) mouse model and conducted endothelial functional assays to explore the role of Sterol Regulatory Element-Binding Protein 1 (SREBF1) in ROP pathogenesis. SREBF1 expression levels, along with its downstream targets, were investigated through Western blotting, RT-qPCR, and immunofluorescence staining techniques. Furthermore, Co-Immunoprecipitation (Co-IP) was employed to examine the molecular mechanisms involved. Our results demonstrated a significant increase in SREBF1 expression in both the OIR mouse model and hypoxic primary human retinal microvascular endothelial cells (HRMECs). Interventions conducted both in vivo and in vitro showed notable efficacy in reducing pathological neovascularization. Importantly, we discovered that SREBF1 plays a key role in modulating lipid metabolism in HRMECs by regulating the expression of ACC1 and FASN, leading to cellular reprogramming. This reprogramming influences HRMEC proliferation, migration, and tube formation through the HIF-1α/TGF-β signaling pathway, ultimately contributing to pathological retinal neovascularization. These findings provide new insights into the role of SREBF1 in angiogenesis within the context of ROP, offering potential therapeutic targets for the management and treatment of this disease.
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Affiliation(s)
- Hangjia Zuo
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, PR China; Chongqing Medical University, Chongqing, PR China
| | - Xianyang Liu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, PR China; Chongqing Medical University, Chongqing, PR China; Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, 100730, China
| | - Yakun Wang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, PR China; Chongqing Medical University, Chongqing, PR China
| | - Huannan Ding
- Chongqing Medical University, Chongqing, PR China
| | - Wenjuan Wan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, PR China; Chongqing Medical University, Chongqing, PR China
| | - Shijie Zheng
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, PR China; Chongqing Medical University, Chongqing, PR China
| | - Shengping Hou
- Chongqing Medical University, Chongqing, PR China; Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, 100730, China.
| | - Ke Hu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Prevention and Treatment on Major Blinding Diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, PR China; Chongqing Medical University, Chongqing, PR China.
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Hu GS, Zheng ZZ, He YH, Wang DC, Nie RC, Liu W. Integrated Analysis of Proteome and Transcriptome Profiling Reveals Pan-Cancer-Associated Pathways and Molecular Biomarkers. Mol Cell Proteomics 2025; 24:100919. [PMID: 39884577 PMCID: PMC11907456 DOI: 10.1016/j.mcpro.2025.100919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 01/02/2025] [Accepted: 01/24/2025] [Indexed: 02/01/2025] Open
Abstract
Understanding dysregulated genes and pathways in cancer is critical for precision oncology. Integrating mass spectrometry-based proteomic data with transcriptomic data presents unique opportunities for systematic analyses of dysregulated genes and pathways in pan-cancer. Here, we compiled a comprehensive set of datasets, encompassing proteomic data from 2404 samples and transcriptomic data from 7752 samples across 13 cancer types. Comparisons between normal or adjacent normal tissues and tumor tissues identified several dysregulated pathways including mRNA splicing, interferon pathway, fatty acid metabolism, and complement coagulation cascade in pan-cancer. Additionally, pan-cancer upregulated and downregulated genes (PCUGs and PCDGs) were also identified. Notably, RRM2 and ADH1B, two genes which belong to PCUGs and PCDGs, respectively, were identified as robust pan-cancer diagnostic biomarkers. TNM stage-based comparisons revealed dysregulated genes and biological pathways involved in cancer progression, among which the dysregulation of complement coagulation cascade and epithelial-mesenchymal transition are frequent in multiple types of cancers. A group of pan-cancer continuously upregulated and downregulated proteins in different tumor stages (PCCUPs and PCCDPs) were identified. We further constructed prognostic risk stratification models for corresponding cancer types based on dysregulated genes, which effectively predict the prognosis for patients with these cancers. Drug prediction based on PCUGs and PCDGs as well as PCCUPs and PCCDPs revealed that small molecule inhibitors targeting CDK, HDAC, MEK, JAK, PI3K, and others might be effective treatments for pan-cancer, thereby supporting drug repurposing. We also developed web tools for cancer diagnosis, pathologic stage assessment, and risk evaluation. Overall, this study highlights the power of combining proteomic and transcriptomic data to identify valuable diagnostic and prognostic markers as well as drug targets and treatments for cancer.
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Affiliation(s)
- Guo-Sheng Hu
- Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou, China; State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Zao-Zao Zheng
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Yao-Hui He
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Du-Chuang Wang
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Rui-Chao Nie
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian, China
| | - Wen Liu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China; National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian, China.
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Zhao Z, Li P, Liu Z, Cui Y, Yao Z, Chen W, Wang M, Yu C, Xia S, Sun Y, Zhang N, Shen W. Exploring the molecular mechanisms by which secretory phospholipase a2 regulates lymphatic endothelial cell dysfunction by activating macrophages. Int J Biol Macromol 2025; 294:139038. [PMID: 39708872 DOI: 10.1016/j.ijbiomac.2024.139038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 12/23/2024]
Abstract
This study offers new insights into the dual role of secretory phospholipase A2 (sPLA2) in lymphedema, highlighting its impact on lymphatic endothelial cell (LEC) functionality. Through transcriptomic analyses and co-culture experiments, we observed that sPLA2 has both protective and detrimental effects on human LECs (HLECs), mediated by macrophage activation. Our findings reveal that while low levels of sPLA2 promote LEC health, excessive sPLA2 leads to dysfunction, emphasizing the significance of the sPLA2/PLA2R axis and arachidonic acid metabolism (AA) in lymphedema pathology. The study suggests targeting sPLA2 and its downstream pathways as a novel therapeutic strategy for lymphedema, aiming to mitigate its progression by safeguarding HLEC integrity. This research underscores the importance of balanced sPLA2 activity in maintaining lymphatic vessel health and presents a new avenue for lymphedema management and treatment.
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Affiliation(s)
- Zimin Zhao
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Peilin Li
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Zhong Liu
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Yonghao Cui
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Zixuan Yao
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Weijian Chen
- Center for Obesity and Metabolic Disease, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Mengqin Wang
- Center for Obesity and Metabolic Disease, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Chengyuan Yu
- Peking University Ninth Clinical School of Medicine, China
| | - Song Xia
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Yuguang Sun
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Nengwei Zhang
- Center for Obesity and Metabolic Disease, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.
| | - Wenbin Shen
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China.
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Luo J, Cai Y, Jia C, Zhang X, Huang Q, Wei J, Chen Q, Chen T. BefA protein alleviates progression of non-alcoholic fatty liver disease by modulating the AMPK signaling pathway through the gut-liver axis. Int J Biol Macromol 2025; 294:139446. [PMID: 39756723 DOI: 10.1016/j.ijbiomac.2024.139446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/29/2024] [Accepted: 12/31/2024] [Indexed: 01/07/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver diseases worldwide, necessitating urgent novel oral treatments. In this study, β-cell expansion factor A (BefA) was evaluated in a murine NAFLD model induced by high-fat diet (HFD). Our results revealed that BefA significantly reduced body weight (36.58 ± 1.55 g vs. 42.30 ± 1.96 g, p < 0.01), fat mass-to-body weight ratio (0.023 ± 0.019 vs. 0.300 ± 0.019, p < 0.05), liver weight (1.90 ± 0.07 g vs. 2.31 ± 0.21 g, p < 0.05), and liver function parameters (ALT, AST, ALP levels reduced, p < 0.05). Notably, BefA reversed the pathological features of NAFLD, decreasing hepatic steatosis score from 3.67 ± 0.47 to 1.67 ± 0.47 (p < 0.01). Mechanistically, BefA activated the AMPK signaling pathway, resulting in the suppression of lipogenic gene transcription (ACC, FASN, SREBP-1c) and the enhancement of fatty acid oxidation (CPT-1, PPAR-α). However, AMPK inhibitor and broad-spectrum antibiotics significantly attenuated the benefits observed with BefA treatment, increasing body weight, fat-to-body weight ratio, and liver weight (p < 0.05). Similar detrimental effects were also observed in liver function indices and histopathological characteristics. These findings underscore the pivotal role of both gut microbiota modulation and AMPK signaling in BefA's therapeutic efficacy, making it a promising multitargeted approach for NAFLD treatment.
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Affiliation(s)
- Jie Luo
- School of Public Health, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Yujie Cai
- Jiangxi Province Key Laboratory of Bioengineering Drugs, School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Chunjian Jia
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Xinfeng Zhang
- Jiangxi Province Key Laboratory of Bioengineering Drugs, School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Qifa Huang
- Department of Obstetrics & Gynecology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Jing Wei
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
| | - Qi Chen
- Department of Obstetrics & Gynecology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
| | - Tingtao Chen
- Jiangxi Province Key Laboratory of Bioengineering Drugs, School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China.
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45
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Ye Z, Sun Y, Yang S, Li L, Li B, Xia Y, Yuan T, Yu W, Chen L, Zhou X, Cheng F. Lgals3 Promotes Calcium Oxalate Crystal Formation and Kidney Injury Through Histone Lactylation-Mediated FGFR4 Activation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413937. [PMID: 39903812 PMCID: PMC11947994 DOI: 10.1002/advs.202413937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/19/2025] [Indexed: 02/06/2025]
Abstract
The incidence of kidney stones is increasing worldwide. However, the underlying mechanism of the process of kidney stone formation and the kidney damage caused are not well understood. Here, it is observed that Lgals3, a β-galactoside-binding protein, is significantly increased in tissues with calcium oxalate (CaOx) stones, and in both in vivo and in vitro models. Lgals3 expression is positively correlated with the deposition of CaOx crystals. Knockout of Lgals3 markedly reduces the deposition of CaOx crystal and renal fibrosis in vivo. Furthermore, Lgals3 deficiency decrease the glycolytic rate and lactate production during the process of CaOx deposition and inhibited histone lactylation of H3K18la. Mechanistic studies shows that Lgals3 directly interacted with the key glycolysis protein pyruvate kinase M2 (PKM2) and promoted its expression by modulating E3 ligase Trim21, preventing the ubiquitination of PKM2. Furthermore, H3K18 lactylation promoted CaOx crystal deposition and kidney injury in vivo and in vitro. Lgals3 deficiency inhibites the transcription, activation, and expression of FGFR4 through inhibition of H3K18la. These findings suggest that Lgals3 may play a key role in CaOx stone formation and kidney injury by interacting with PKM2 and promoting both H3K18la-mediated gene transcription and activation.
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Affiliation(s)
- Zehua Ye
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
| | - Yushi Sun
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
| | - Songyuan Yang
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
| | - Lei Li
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
| | - Bojun Li
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
| | - Yuqi Xia
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
| | - Tianhui Yuan
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
| | - Weimin Yu
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
| | - Lijia Chen
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
| | - Xiangjun Zhou
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
| | - Fan Cheng
- Department of UrologyRenmin hospital of Wuhan universityWuhan430060China
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46
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Wu B, Liu Y, Li H, Zhu L, Zeng L, Zhang Z, Peng W. Liver as a new target organ in Alzheimer's disease: insight from cholesterol metabolism and its role in amyloid-beta clearance. Neural Regen Res 2025; 20:695-714. [PMID: 38886936 PMCID: PMC11433892 DOI: 10.4103/1673-5374.391305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/14/2023] [Accepted: 11/07/2023] [Indexed: 06/20/2024] Open
Abstract
Alzheimer's disease, the primary cause of dementia, is characterized by neuropathologies, such as amyloid plaques, synaptic and neuronal degeneration, and neurofibrillary tangles. Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs, targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment. Metabolic abnormalities are commonly observed in patients with Alzheimer's disease. The liver is the primary peripheral organ involved in amyloid-beta metabolism, playing a crucial role in the pathophysiology of Alzheimer's disease. Notably, impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease. In this review, we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism. Furthermore, we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.
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Affiliation(s)
- Beibei Wu
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yuqing Liu
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Hongli Li
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Lemei Zhu
- Academician Workstation, Changsha Medical University, Changsha, Hunan Province, China
| | - Lingfeng Zeng
- Academician Workstation, Changsha Medical University, Changsha, Hunan Province, China
| | - Zhen Zhang
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- Yangsheng College of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, China
- Qinhuangdao Shanhaiguan Pharmaceutical Co., Ltd, Qinhuangdao, Hebei Province, China
| | - Weijun Peng
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- National Clinical Research Center for Mental Disorder, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
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Wang L, Duan W, Ruan C, Liu J, Miyagishi M, Kasim V, Wu S. YY2-CYP51A1 signaling suppresses hepatocellular carcinoma progression by restraining de novo cholesterol biosynthesis. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167658. [PMID: 39761760 DOI: 10.1016/j.bbadis.2025.167658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/11/2024] [Accepted: 01/02/2025] [Indexed: 01/12/2025]
Abstract
Lipid accumulation is a frequently observed characteristic of cancer. Lipid accumulation is closely related to tumor progression, metastasis, and drug resistance; however, the mechanism underlying lipid metabolic reprogramming in tumor cells is not fully understood. Yin yang 2 (YY2) is a C2H2‑zinc finger transcription factor that exerts tumor-suppressive effects. However, its involvement in tumor cell lipid metabolic reprogramming remains unclear. In the present study, we identified YY2 as a novel regulator of cholesterol metabolism. We showed that YY2 suppressed cholesterol accumulation in hepatocellular carcinoma (HCC) cells by downregulating the transcriptional activity of cytochrome P450 family 51 subfamily A member 1 (CYP51A1), a key enzyme in de novo cholesterol biosynthesis. Subsequently, through in vitro and in vivo experiments, we demonstrated that this downregulation is crucial for the YY2 tumor suppressive effect. Together, our findings unraveled a previously unprecedented regulation of HCC cells cholesterol metabolism, and eventually, their tumorigenic potential, through YY2 negative regulation on CYP51A1 expression. This study revealed a novel regulatory mechanism of lipid metabolic reprogramming in tumor cells and provided insights into the molecular mechanism underlying the YY2 the suppressive effect. Furthermore, our findings suggest a potential antitumor therapeutic strategy targeting cholesterol metabolic reprogramming using YY2.
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Affiliation(s)
- Lingxian Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Wei Duan
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Cao Ruan
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Jingyi Liu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Makoto Miyagishi
- Life Science Innovation, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki 305-0006, Japan
| | - Vivi Kasim
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China; Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China.
| | - Shourong Wu
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China; Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China.
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48
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Qu H, Wang C, Sun S, Zhang W, Liu C, Du X, Shu Y, Wang X, Pan Q, Luo F, Wu H, Zhang X, Liu M. Bioinformatics Identification of Lactate-Associated Genes in Hepatocellular Carcinoma: G6PD's Role in Immune Modulation. Cancer Med 2025; 14:e70801. [PMID: 40116585 PMCID: PMC11927016 DOI: 10.1002/cam4.70801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 03/08/2025] [Accepted: 03/11/2025] [Indexed: 03/23/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major global health issue, with poor prognosis often associated with dysregulated metabolic pathways, especially lactate metabolism. This study explored the prognostic significance of lactate-associated genes in HCC and their potential as therapeutic targets. METHODS We analyzed RNA-seq and clinical data from 374 patients with HCC from The Cancer Genome Atlas (TCGA) database. Using Cox regression, LASSO analysis, and Kaplan-Meier survival curves, we identified key lactate-associated genes associated with patient outcomes. Functional validations, including Western blot, flow cytometry, and molecular docking studies, were performed to confirm the biological impact of these genes. RESULTS G6PD, IK, and CALML5 were identified as significant prognostic markers for HCC. A prognostic model was developed that effectively stratified patients into risk groups, which correlated with survival. G6PD's role in immune modulation and its potential as a drug target were validated through biochemical assays and computational analyses. Functional assays in HepG2 cells confirmed that alterations in G6PD expression affect T cell activity, with knockdown enhancing IFN-γ production and overexpression inhibiting it, demonstrating G6PD's role in immune evasion. CONCLUSIONS This study establishes lactate metabolism genes, particularly G6PD, as key prognostic markers in HCC. The validation of G6PD's immunomodulatory effects further supports its potential as a therapeutic target for strategies aimed at enhancing immune surveillance and treatment outcomes in HCC.
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Affiliation(s)
- Hao‐ran Qu
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
- Frontier Science Center for Immunology and Metabolism, Department of Allergy Zhongnan HospitalWuhan University School of MedicineWuhanChina
| | - Chao‐qun Wang
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanChina
- Central LaboratoryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Su‐juan Sun
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
- Frontier Science Center for Immunology and Metabolism, Department of Allergy Zhongnan HospitalWuhan University School of MedicineWuhanChina
| | - Wen‐wen Zhang
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
- Frontier Science Center for Immunology and Metabolism, Department of Allergy Zhongnan HospitalWuhan University School of MedicineWuhanChina
| | - Cheng‐hao Liu
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
| | - Xuan‐shuang Du
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
- Frontier Science Center for Immunology and Metabolism, Department of Allergy Zhongnan HospitalWuhan University School of MedicineWuhanChina
| | - Yao‐yi‐ao Shu
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanChina
- Central LaboratoryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Xi‐cheng Wang
- Department of NeurosurgeryRenmin Hospital of Wuhan UniversityWuhanChina
- Central LaboratoryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Qin Pan
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
- Frontier Science Center for Immunology and Metabolism, Department of Allergy Zhongnan HospitalWuhan University School of MedicineWuhanChina
| | - Feng‐ling Luo
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
- Frontier Science Center for Immunology and Metabolism, Department of Allergy Zhongnan HospitalWuhan University School of MedicineWuhanChina
| | - Hong‐yan Wu
- Hubei Key Laboratory of Tumor Microenvironment and ImmunotherapyChina Three Gorges UniversityYichangChina
- School of Basic MedicineChina Three Gorges UniversityYichangChina
| | - Xiao‐lian Zhang
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
- Frontier Science Center for Immunology and Metabolism, Department of Allergy Zhongnan HospitalWuhan University School of MedicineWuhanChina
| | - Min Liu
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences)Wuhan UniversityWuhanChina
- Frontier Science Center for Immunology and Metabolism, Department of Allergy Zhongnan HospitalWuhan University School of MedicineWuhanChina
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Yin Q, Yao Y, Ni J, Zhang Y, Wu J, Zeng H, Wu W, Zhuo W, Ying J, Li J. DLAT activates EMT to promote HCC metastasis by regulating GLUT1-mediated aerobic glycolysis. Mol Med 2025; 31:71. [PMID: 39979835 PMCID: PMC11844032 DOI: 10.1186/s10020-025-01125-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 02/11/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC) progression, driving aberrant cellular processes in response to pathological stimuli. While dihydrolipoyl transacetylase (DLAT) has been implicated in the development of various cancers, its specific role and underlying mechanisms in HCC remain unclear. This study aimed to investigate the expression, function, and mechanistic impact of DLAT in HCC. METHODS A comprehensive analysis was conducted using RNA sequencing data, tissue microarrays, in vitro and in vivo functional assays, and mechanistic studies to evaluate DLAT expression, its functional role in tumor progression, and associated molecular pathways in HCC. RESULTS Our study revealed a significant upregulation of DLAT expression in HCC, which was linked to a poor prognosis. Furthermore, we discovered that DLAT facilitated tumor metastasis by driving metabolic reprogramming in HCC cells. Mechanistically, DLAT was found to enhance glucose transporter 1 (GLUT1) expression via H3K18 acetylation, thereby promoting aerobic glycolysis and epithelial-to-mesenchymal transition (EMT), which subsequently augmented metastasis of HCC both in vitro and in vivo. Finally, we confirmed a positive correlation between DLAT and GLUT1 expression in HCC tissues. CONCLUSIONS These findings establish DLAT as a key regulator in HCC progression and suggest its potential as a promising predictive biomarker and therapeutic target for improving HCC diagnosis and treatment.
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Affiliation(s)
- Qian Yin
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, 310022, Zhejiang, China
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, P. R. China
| | - Yinye Yao
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, 310022, Zhejiang, China
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, P. R. China
| | - Jiaojiao Ni
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, P. R. China
| | - Yiwen Zhang
- Zhejiang Provincial Clinical Research Center for Malignant Tumor, Hangzhou, 310014, Zhejiang, P. R. China
| | - Jia Wu
- Hepatobiliary and Pancreatic Surgery Department, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, Zhejiang, P. R. China
| | - Hui Zeng
- Department of Interventional Radiology, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, P. R. China
| | - Wei Wu
- Department of Pathology, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, Zhejiang, P. R. China
| | - Wei Zhuo
- Department of Cell Biology, Department of Colorectal Surgery and Oncology, Center for Medical Research and Innovation in Digestive System Tumors, The Second Affiliated Hospital, Cancer Center, Ministry of Education, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Jieer Ying
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, 310022, Zhejiang, China.
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, P. R. China.
| | - Jingjing Li
- Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, P. R. China.
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Yang H, Li J, Niu Y, Zhou T, Zhang P, Liu Y, Li Y. Interactions between the metabolic reprogramming of liver cancer and tumor microenvironment. Front Immunol 2025; 16:1494788. [PMID: 40028341 PMCID: PMC11868052 DOI: 10.3389/fimmu.2025.1494788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 01/29/2025] [Indexed: 03/05/2025] Open
Abstract
Metabolic reprogramming is one of the major biological features of malignant tumors, playing a crucial role in the initiation and progression of cancer. The tumor microenvironment consists of various non-cancer cells, such as hepatic stellate cells, cancer-associated fibroblasts (CAFs), immune cells, as well as extracellular matrix and soluble substances. In liver cancer, metabolic reprogramming not only affects its own growth and survival but also interacts with other non-cancer cells by influencing the expression and release of metabolites and cytokines (such as lactate, PGE2, arginine). This interaction leads to acidification of the microenvironment and restricts the uptake of nutrients by other non-cancer cells, resulting in metabolic competition and symbiosis. At the same time, metabolic reprogramming in neighboring cells during proliferation and differentiation processes also impacts tumor immunity. This article provides a comprehensive overview of the metabolic crosstalk between liver cancer cells and their tumor microenvironment, deepening our understanding of relevant findings and pathways. This contributes to further understanding the regulation of cancer development and immune evasion mechanisms while providing assistance in advancing personalized therapies targeting metabolic pathways for anti-cancer treatment.
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Affiliation(s)
- Haoqiang Yang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Jinghui Li
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yiting Niu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Tao Zhou
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Pengyu Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yang Liu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yanjun Li
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, TongjiShanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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