1
|
Yue X, Wang Y, Zheng R, Li L. The coping experiences in patients with hepatocellular carcinoma and their spouses following postoperative recurrence: A dyadic qualitative study. Asia Pac J Oncol Nurs 2025; 12:100665. [PMID: 40104041 PMCID: PMC11919323 DOI: 10.1016/j.apjon.2025.100665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 02/05/2025] [Indexed: 03/20/2025] Open
Abstract
Objective Dyadic coping practices can vary depending on cultural contexts, socioeconomic factors, and the stages of the cancer journey. This study aimed to explore the dyadic coping experiences of hepatocellular carcinoma (HCC) patients and their spouses following postoperative recurrence in the Chinese cultural context, where cancer recurrence is frequently seen as a death sentence, and family-centered care is prioritized. Methods A descriptive qualitative research design was used, involving face-to-face, in-depth semi-structured interviews with 13 pairs of hepatocellular carcinoma patients and their spouses at a tertiary cancer hospital from July to October 2023. The interview guide was designed based on the Actor-Partner Interdependence Model (APIM) framework. Data were analyzed using thematic analysis, and the study adhered to the COnsolidated criteria for REporting Qualitative research (COREQ) checklist. Results Three themes were identified: (1) active coping strategies, (2) negative coping tendencies, and (3) the need for systematic coping support. The majority of couples perceived hepatocellular carcinoma recurrence as a death sentence, which prompted them-especially the spouses-to adopt proactive strategies, such as striving to seek advanced treatments and concealing unfavorable information. In contrast, patients, particularly those with a hereditary hepatocellular carcinoma background, often exhibited passivity, withdrawal, and contemplation of treatment abandonment. Spouses frequently felt overwhelmed and unable to alleviate their partners' anxiety about recurrence and death, particularly in the absence of support from health care professionals. They expressed a strong need for professional guidance and targeted interventions to address end-of-life concerns, emphasizing the need for increased financial support, empowerment through knowledge, and access to peer support networks. Conclusions This research emphasizes the importance of recognizing the interdependent coping experiences of recurrent HCC patients and their spouses. Health care professionals are encouraged to implement culturally sensitive, dyadic interventions that foster collaborative coping, address death-related anxiety, and empower couples in managing recurrence together, thereby enhancing their coping strategies and confidence.
Collapse
Affiliation(s)
- Xian Yue
- Department of Nursing, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yanhui Wang
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ruishuang Zheng
- Department of Hepatobiliary, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Laiyou Li
- Department of Nursing, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| |
Collapse
|
2
|
Wang J, Qiu K, Zhou S, Gan Y, Jiang K, Wang D, Wang H. Risk factors for hepatocellular carcinoma: an umbrella review of systematic review and meta-analysis. Ann Med 2025; 57:2455539. [PMID: 39834076 PMCID: PMC11753015 DOI: 10.1080/07853890.2025.2455539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Numerous meta-analyses have identified various risk factors for hepatocellular carcinoma (HCC), prompting a comprehensive study to synthesize evidence quality and strength. METHODS This umbrella review of meta-analyses was conducted throughout PubMed, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews. Evidence strength was evaluated according to the evidence categories criteria. RESULTS We identified 101 risk factors throughout 175 meta-analyses. 31 risk factors were classified as evidence levels of class I, II, or III. HBV and HCV infections increase HCC risk by 12.5-fold and 11.2-fold, respectively. These risks are moderated by antiviral treatments and virological responses but are exacerbated by higher HBsAg levels, anti-HBc positivity, and co-infection. Smoking, obesity, non-alcoholic fatty liver disease, diabetes, low platelet, elevated liver enzymes and liver fluke infection increase HCC risk, while coffee consumption, a healthy diet, and bariatric surgery lower it. Medications like metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), aspirin, statins, and selective serotonin reuptake inhibitors reduce HCC risk, while acid suppressive agents, particularly proton pump inhibitors, elevate it. Blood type O reduces the risk of HCC, while male gender and older age increase the risk. CONCLUSIONS HBV and HCV are major HCC risk factors, with risk mitigation through antiviral treatments. Lifestyle habits such as smoking and alcohol use significantly increase HCC risk, highlighting the importance of cessation. Certain drugs like aspirin, statins, GLP-1 RAs, and metformin may reduce HCC occurrence, but further research is needed to confirm these effects.
Collapse
Affiliation(s)
- Jie Wang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Kaijie Qiu
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Songsheng Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Yichao Gan
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Keting Jiang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Donghuan Wang
- Operations Department, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Haibiao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| |
Collapse
|
3
|
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.
Collapse
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
| |
Collapse
|
4
|
Liu M, Ke M, Lu H, Feng Z, Wang K, Wang D, Wang K, Bai Y, Yang S, Miao L, Chen Q, Sun M, Shan C, Hu J, Jiang L, Jin H, Hu J, Huang C, Wang R, Zhao W, Yu F. A novel cinnamic acid derivative for hepatocellular carcinoma therapy by degrading METTL16 protein. Bioorg Med Chem 2025; 124:118178. [PMID: 40186923 DOI: 10.1016/j.bmc.2025.118178] [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: 02/11/2025] [Revised: 03/26/2025] [Accepted: 03/28/2025] [Indexed: 04/07/2025]
Abstract
The RNA methyltransferase methyltransferaselike protein 16 (METTL16) is upregulated in a large proportion of hepatocellular carcinoma (HCC), and its high expression is associated with poor clinical outcomes. METTL16 deletion inhibits HCC growth in vitro and in vivo. Referencing the structure of cinnamic acid, here we designed and synthesized a novel series of small molecular compounds, and found through bioactivity screening that compound 15a effectively reduced METTL16 level and modulated oncogenic PI3K/AKT pathway signaling. Compound 15a inhibited the proliferation and migration of HepG2 cells, and induced apoptosis in vitro. Furthermore, compound 15a significantly inhibited the growth of patient-derived HCC xenografts in nude mice with greater efficacy than the multi-kinase inhibitor lenvatinib. The promising efficacy and good biosafety profile of compound 15a enables us to further develop this compound for treating patients with HCC and possibly other cancers in clinic.
Collapse
Affiliation(s)
- Mingyang Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Muyan Ke
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Hongchen Lu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Ziyu Feng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Kaixuan Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Danyang Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Kun Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Yueping Bai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China; Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369 Dengyun Road, Qingdao 266113, China
| | - Song Yang
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369 Dengyun Road, Qingdao 266113, China
| | - Lu Miao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Qiang Chen
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Mingming Sun
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Changliang Shan
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China.
| | - Jiancheng Hu
- Cancer and Stem Cell Program, Duke-NUS Medical School, 8 College Road, 169857 Singapore, Singapore.
| | - Lingyu Jiang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China
| | - Hongzhen Jin
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369 Dengyun Road, Qingdao 266113, China
| | - Jinfang Hu
- State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Tiancheng Drug Assessment Co., Ltd, Tianjin 300193, Chinaa.
| | - Changjiang Huang
- State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Tiancheng Drug Assessment Co., Ltd, Tianjin 300193, Chinaa.
| | - Rui Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China.
| | - Wei Zhao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China; Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369 Dengyun Road, Qingdao 266113, China; Frontiers Science Center for New Organic Matter, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China.
| | - Fan Yu
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369 Dengyun Road, Qingdao 266113, China.
| |
Collapse
|
5
|
Luo Y, Yang Q, Hu J, Qin X, Jiang S, Liu Y. Preliminary study on detection and diagnosis of focal liver lesions based on a deep learning model using multimodal PET/CT images. Eur J Radiol Open 2025; 14:100624. [PMID: 39803389 PMCID: PMC11720101 DOI: 10.1016/j.ejro.2024.100624] [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: 06/17/2024] [Revised: 10/23/2024] [Accepted: 12/11/2024] [Indexed: 01/16/2025] Open
Abstract
Objectives To develop and validate a deep learning model using multimodal PET/CT imaging for detecting and classifying focal liver lesions (FLL). Methods This study included 185 patients who underwent 18F-FDG PET/CT imaging at our institution from March 2022 to February 2023. We analyzed serological data and imaging. Liver lesions were segmented on PET and CT, serving as the "reference standard". Deep learning models were trained using PET and CT images to generate predicted segmentations and classify lesion nature. Model performance was evaluated by comparing the predicted segmentations with the reference segmentations, using metrics such as Dice, Precision, Recall, F1-score, ROC, and AUC, and compared it with physician diagnoses. Results This study finally included 150 patients, comprising 46 patients with benign liver nodules, 51 patients with malignant liver nodules, and 53 patients with no FLLs. Significant differences were observed among groups for age, AST, ALP, GGT, AFP, CA19-9and CEA. On the validation set, the Dice coefficient of the model was 0.740. For the normal group, the recall was 0.918, precision was 0.904, F1-score was 0.909, and AUC was 0.976. For the benign group, the recall was 0.869, precision was 0.862, F1-score was 0.863, and AUC was 0.928. For the malignant group, the recall was 0.858, precision was 0.914, F1-score was 0.883, and AUC was 0.979. The model's overall diagnostic performance was between that of junior and senior physician. Conclusion This deep learning model demonstrated high sensitivity in detecting FLLs and effectively differentiated between benign and malignant lesions.
Collapse
Affiliation(s)
- Yingqi Luo
- Department of Nuclear medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Qingqi Yang
- Department of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jinglang Hu
- School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Xiaowen Qin
- Department of Nuclear medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Shengnan Jiang
- Department of Nuclear medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ying Liu
- Department of Nuclear medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
6
|
Qi M, Zhang K, Zhang X, Zhu Y, Cai B, Wang C, Zhao G, Zhang D, Zhang J. Arginine tagged liposomal carrier for the delivery of celastrol for ferroptosis-induced hepatocellular carcinoma therapy. Colloids Surf B Biointerfaces 2025; 250:114546. [PMID: 39919344 DOI: 10.1016/j.colsurfb.2025.114546] [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: 10/10/2024] [Revised: 01/21/2025] [Accepted: 01/31/2025] [Indexed: 02/09/2025]
Abstract
Hepatocellular carcinoma (HCC) is a predominant malignant liver tumor that cannot be efficiently treated because of poor response, toxicity, and drug resistance. Ferroptosis is an iron-dependent way of cell death associated with abnormal intracellular lipid metabolism. Celastrol (Cel) has the ability to inhibit the progression of HCC by regulating multiple signaling pathways and induce ferroptosis. However, Cel exists the limitations of low water solubility, low oral bioavailability, and high organ toxicity. Cel was encapsulated in polyethylene glycol-based liposomes modified with L-arginine (Cel@Lip-Arg). Cel@Lip-Arg has a uniform size distribution (∼100 nm), high drug loading (80 %), and excellent ability to target liver cancer cells. In vitro experiments demonstrated that Cel@Lip-Arg considerably suppressed the activity of HuH7 (hepatoma) cells but had a negligible effect on L02 (normal) cells. Cel@Lip-Arg induced ferroptosis in hepatoma cells by promoting transferrin receptor expression, inhibiting system xc- and glutathione peroxidase 4, and favoring intracellular peroxide accumulation. In vivo experiments revealed that Cel@Lip-Arg plays a therapeutic role by inducing ferroptosis. Compared to Cel, Cel@Lip-Arg had a higher anti-hepatoma activity and effectively reduced the toxicity of Cel in mice. Cel@Lip-Arg-induced ferroptosis was concluded to be an attractive strategy for the precise treatment of HCC.
Collapse
Affiliation(s)
- Manman Qi
- School of Medicine, Shanghai University, Shanghai 200444, PR China
| | - Kai Zhang
- School of Medicine, Shanghai University, Shanghai 200444, PR China
| | - Xue Zhang
- School of Basic Medicine, Ningxia Medical University, Ningxia 750004, PR China
| | - Yuzhao Zhu
- Shanghai Universal Medical Imaging Diagnostic Center, Shanghai University, Shanghai 200233, PR China
| | - Banglan Cai
- School of Basic Medicine, Ningxia Medical University, Ningxia 750004, PR China
| | - Chao Wang
- Shanghai Universal Medical Imaging Diagnostic Center, Shanghai University, Shanghai 200233, PR China
| | - Gang Zhao
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, PR China.
| | - Denghai Zhang
- School of Medicine, Shanghai University, Shanghai 200444, PR China.
| | - Jian Zhang
- School of Medicine, Shanghai University, Shanghai 200444, PR China; Shanghai Universal Medical Imaging Diagnostic Center, Shanghai University, Shanghai 200233, PR China.
| |
Collapse
|
7
|
Pan X, Wang B, Fang S. Comment on Kim (2025) 'Survivorship concerns among posttreatment cancer survivors in South Korea: A secondary analysis of a cross-sectional survey'. Int J Nurs Stud 2025; 166:105040. [PMID: 40155276 DOI: 10.1016/j.ijnurstu.2025.105040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 02/25/2025] [Indexed: 04/01/2025]
Affiliation(s)
- Xiaona Pan
- Department of Nursing, Tongling People's Hospital, Tongling, Anhui, China
| | - Bo Wang
- Department of Nursing, Tongling People's Hospital, Tongling, Anhui, China
| | - Shuling Fang
- Department of Nursing, Tongling People's Hospital, Tongling, Anhui, China.
| |
Collapse
|
8
|
Artusa F, Lamatsch S, Phan MD, Özdirik B, Berger H, Egerer M, Knorr‐Klocke J, Fischer J, Veelken R, van Bömmel F, Berg T, Kappert K, Tauber R, Puengel T, Engelmann C, Demir M, Tacke F, Mohr R. Soluble Urokinase Plasminogen Activator Receptor Predicts Survival and Hepatic Decompensation in Advanced Hepatocellular Carcinoma. Liver Int 2025; 45:e70121. [PMID: 40317602 PMCID: PMC12046945 DOI: 10.1111/liv.70121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 04/01/2025] [Accepted: 04/22/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND AND AIMS The introduction of immune checkpoint inhibitor (ICI) based therapies has significantly improved the prognosis of patients with unresectable hepatocellular carcinoma (HCC). However, the variable treatment response and the uncertain benefit in patients with advanced liver cirrhosis emphasise the urgent need for prognostic and predictive biomarkers guiding patient selection. The soluble urokinase plasminogen activator receptor (suPAR) is strongly associated with inflammation, liver cirrhosis and various types of cancer. In this study, we investigated suPAR as a potential novel biomarker in patients with unresectable HCC. METHODS This multicenter retrospective study, conducted at three German tertiary care centers, included 90 patients with unresectable HCC and suPAR measurements prior to and during atezolizumab/bevacizumab therapy. Patients with liver cirrhosis without HCC (n = 235) and non-cirrhotic patients with other gastrointestinal tumours (n = 155) were selected as control cohorts. RESULTS Median suPAR levels were significantly higher in patients with liver cirrhosis compared to non-cirrhotic cancer patients. A strong association with parameters of liver function, but not with HCC characteristics, was observed. In patients with HCC receiving atezolizumab/bevacizumab, suPAR was the most accurate independent predictor of hepatic decompensation and overall survival (OS). In addition, suPAR was able to stratify the risk of hepatic decompensation within the different Child-Pugh classes. CONCLUSIONS SuPAR represents a promising novel biomarker in patients with HCC treated with ICI-based therapies and bears the potential to guide the selection of antitumoral systemic therapies in patients with advanced liver cirrhosis.
Collapse
Affiliation(s)
- Fabian Artusa
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Sven Lamatsch
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Minh Duc Phan
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Burcin Özdirik
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Hilmar Berger
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Mara Egerer
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Jana Knorr‐Klocke
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Janett Fischer
- Division of Hepatology, Department of Medicine IILeipzig University Medical CenterLeipzigGermany
| | - Rhea Veelken
- Division of Hepatology, Department of Medicine IILeipzig University Medical CenterLeipzigGermany
| | - Florian van Bömmel
- Division of Hepatology, Department of Medicine IILeipzig University Medical CenterLeipzigGermany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine IILeipzig University Medical CenterLeipzigGermany
| | - Kai Kappert
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and PathobiochemistryCharité ‐ Universitätsmedizin BerlinBerlinGermany
- Labor Berlin – Charité Vivantes GmbHBerlinGermany
| | - Rudolf Tauber
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and PathobiochemistryCharité ‐ Universitätsmedizin BerlinBerlinGermany
- Labor Berlin – Charité Vivantes GmbHBerlinGermany
| | - Tobias Puengel
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Cornelius Engelmann
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
- Institute for Liver and Digestive HealthUniversity College LondonLondonUK
| | - Münevver Demir
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Frank Tacke
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| | - Raphael Mohr
- Department of Hepatology and GastroenterologyCharité ‐ Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM)BerlinGermany
| |
Collapse
|
9
|
Liu Q, Liang Z, Wang J, Wang Y, Wang J, Wang S, Du Z, Zhao L, Wei Y, Huang D. Mannose-modified multifunctional iron-based nanozyme for hepatocellular carcinoma treatment by remodeling the tumor microenvironment. Colloids Surf B Biointerfaces 2025; 250:114548. [PMID: 39923382 DOI: 10.1016/j.colsurfb.2025.114548] [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: 10/19/2024] [Revised: 01/12/2025] [Accepted: 01/31/2025] [Indexed: 02/11/2025]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, with conventional treatments often accompanied by severe side effects. Recently, nanozymes have been extensively employed in cancer therapy due to their enhanced enzymatic activities, stability compared to native enzymes. However, a standalone nanozyme exhibits insufficient targeting capability and fails to specifically localize to the pathological site. In this study, we successfully synthesized a multifunctional iron-based-nanozyme delivery system - Fe3O4-OA-DHCA-PEI-MAN@DSF modified with PEI and MAN by the thermal decomposition method. This mannose-modified nanozyme can specifically target HCC cells via an external magnetic field and mannose-mannose receptor (MRC2) binding. In addition, it exhibits good biocompatibility and pH-dependent drug release characteristics. Within the acidic tumor microenvironment, the iron-based nanozyme initiates intracellular fenton reactions, boosting reactive oxygen species (ROS) production, which ultimately induces apoptosis in HCC cells. Concurrently, the disulfiram small molecule released from the Fe3O4-OA-DHCA-PEI-MAN@DSF nanozyme binds to the FROUNT factor within monocyte-macrophages, thereby inhibiting their response to chemotactic signals emitted by liver cancer cells. This process ultimately suppresses the recruitment of macrophages by HCC cells, reshaping the tumor microenvironment and supporting effective liver cancer treatment. Moreover, this nanozyme system holds potential for MRI-guided targeted chemotherapy combined with chemodynamic therapy, aiming to refine the early diagnosis and precision treatment of hepatic carcinoma, and paving the way for the creation of sophisticated integrated nanoplatforms melding diagnostic and therapeutic functionalities.
Collapse
Affiliation(s)
- Qi Liu
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Artificial Intelligence, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan 030024, China
| | - Ziwei Liang
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Artificial Intelligence, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan 030024, China; NHC Key Laboratory of Glycoconjuates Research Department of Biochemistry and Molecular, Biology School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan 030032, China; Shanxi Provincial Key Laboratory for Functional Proteins, Shanxi Jinbo Bio-Pharmaceutical Co., Ltd, Taiyuan 030032, China.
| | - Jiapu Wang
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Artificial Intelligence, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan 030024, China
| | - Yuhui Wang
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Artificial Intelligence, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan 030024, China
| | - Jie Wang
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Artificial Intelligence, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan 030024, China
| | - Shaojie Wang
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Artificial Intelligence, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan 030024, China
| | - Zhi Du
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Artificial Intelligence, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan 030024, China; Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan 030032, China
| | - Liqin Zhao
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Artificial Intelligence, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan 030024, China; Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan 030032, China
| | - Yan Wei
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Artificial Intelligence, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan 030024, China; Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan 030032, China; Shanxi Provincial Key Laboratory for Functional Proteins, Shanxi Jinbo Bio-Pharmaceutical Co., Ltd, Taiyuan 030032, China.
| | - Di Huang
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Artificial Intelligence, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan 030024, China; Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan 030032, China; Shanxi Provincial Key Laboratory for Functional Proteins, Shanxi Jinbo Bio-Pharmaceutical Co., Ltd, Taiyuan 030032, China.
| |
Collapse
|
10
|
Karampera C, D'Alessio A. Not So Quiet on the Viral Front: Low-Level HBV Viraemia Undermines Immunotherapy in HCC. Liver Int 2025; 45:e70140. [PMID: 40356364 DOI: 10.1111/liv.70140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2025] [Accepted: 05/04/2025] [Indexed: 05/15/2025]
Affiliation(s)
- Christina Karampera
- Liver Unit, King's College Hospital, London, UK
- Centre of Cancer Evolution, Bart's Cancer Institute, Queen Mary University of London, London, UK
| | - Antonio D'Alessio
- Liver Unit, King's College Hospital, London, UK
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| |
Collapse
|
11
|
Wang MD, Wang BD, Diao YK, Li C, Yao LQ, Liu H, Zeng YY, Chen Z, Wu H, Xu XF, Gu LH, Xu JH, Yin DX, Li YC, Chen FJ, Kow AWC, Pawlik TM, Shen F, Yang T. Tumor biology characteristics score based on alpha-fetoprotein and protein induced by vitamin K absence or antagonist II as a predictor for recurrence and survival after curative resection for hepatocellular carcinoma: a multicenter cohort study. J Gastrointest Surg 2025; 29:102038. [PMID: 40157713 DOI: 10.1016/j.gassur.2025.102038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 03/03/2025] [Accepted: 03/22/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND Current hepatocellular carcinoma (HCC) staging systems lack comprehensive assessment of tumor biologic characteristics. This study aimed to develop and validate a tumor biology characteristics score (TBCS) based on alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II) to predict long-term oncologic outcomes after HCC resection. METHODS In this multicenter retrospective cohort study, patients who underwent curative resection for HCC between June 2018 and December 2022 were included. TBCS (range, 2-6 points) was calculated by combining preoperative AFP (<20, 20-199, and ≥200 ng/mL) and PIVKA-II levels (<40, 40-399, and ≥400 mAU/mL). Patients were stratified into low (2 points), medium (3-4 points), and high TBCS groups (5-6 points). The primary outcomes were recurrence-free survival (RFS) and overall survival (OS). RESULTS A total of 695 patients were analyzed; the low, medium, and high TBCS groups comprised 132 (19.0%), 233 (33.5%), and 330 patients (47.5%), respectively. Notably, 5-year RFS was 30.4%, 14.7%, and 9.7%, whereas 5-year OS was 42.1%, 35.5%, and 23.5% for low, medium, and high TBCS groups, respectively (both P <.001). Multivariate analysis identified TBCS as an independent predictor of both RFS (medium TBCS: hazard ratio [HR], 1.583; 95% CI, 1.219-2.057; P =.001; high TBCS: HR, 1.895; 95% CI, 1.473-2.438; P <.001) and OS (high TBCS: HR, 1.781; 95% CI, 1.353-2.343; P <.001). CONCLUSION The novel TBCS combining AFP and PIVKA-II effectively stratified patients with HCC into distinct prognostic groups after curative-intent resection, independently predicting both RFS and OS. This score may help identify high-risk patients for more intense postoperative recurrence surveillance and receipt of adjuvant therapies.
Collapse
Affiliation(s)
- Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Bai-Dong Wang
- Second Military Medical University (Naval Medical University), Shanghai, China
| | - Yong-Kang Diao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Lan-Qing Yao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Han Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Centre, First Hospital of Jilin University, Changchun, Jilin, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, China
| | - Zhong Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Xin-Fei Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Li-Hui Gu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Jia-Hao Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Dong-Xu Yin
- School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yu-Chen Li
- Department of Graduate, Bengbu Medical University, Bengbu, Anhui, China
| | - Fu-Jie Chen
- Department of Graduate, Bengbu Medical University, Bengbu, Anhui, China
| | - Alfred Wei Chieh Kow
- Division of Hepatopancreaticobiliary Surgery and Liver Transplantation, Department of Surgery, National University Health System, Singapore, Singapore
| | - Timothy M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Centre, Columbus, OH, United States
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Naval Medical University, Shanghai, China.
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China; School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, China; Department of Graduate, Bengbu Medical University, Bengbu, Anhui, China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Naval Medical University, Shanghai, China.
| |
Collapse
|
12
|
Zhu H, Wang G, Liao Z, Zhang W. AITL-Net: An adaptive interpretable transfer learning network with robust generalization for liver cancer recognition. Knowl Based Syst 2025; 318:113473. [DOI: 10.1016/j.knosys.2025.113473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
|
13
|
Gao X, Bian T, Wei X, Xu M, Ren J, Zhao Y, Zheng Y, Li X. Exploration of mechanism of Bufalin and Bufalin derivatives in hepatocellular carcinoma. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156686. [PMID: 40220402 DOI: 10.1016/j.phymed.2025.156686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/11/2025] [Accepted: 03/24/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Bufalin, a promising candidate for the treatment of hepatocellular carcinoma (HCC), has garnered interest from researchers in exploring its pharmacological mechanisms. The traditional single-target research method makes it difficult to elucidate the molecular mechanism systematically, and there are still limitations. PURPOSE To explore the synergistic mechanisms of Bufalin and its derivatives in the treatment of HCC through quantitative and integrated analysis of big data, this study provides a reference for clinical screening of anti-liver cancer drugs and accelerates the research and development of new drugs. METHODS The literature on the anti-liver cancer activity of Bufalin was searched, the research trends and hotspots were analyzed, and the hot targets were identified. Potential targets and signaling pathways were predicted and compared with established targets. To evaluate the affinity of Bufalin and its derivatives with key targets and validate the results of network pharmacology. The structure-activity relationships and pathways were reviewed, and key pharmacophore and potential pathways were identified. RESULTS Analysis of 302 literatures showed that Na+/K+-ATPase was a hot target in the anti-liver cancer mechanism of Bufalin. 76 potential targets are primarily associated with pathways such as PI3K/AKT/mTOR, Hedgehog, and AMPK/mTOR, which play roles in regulating key targets like phosphoinositide 3-kinase (PIK3), adenosine monophosphate-activated protein kinase (AMPK), and epidermal growth factor receptor (EGFR). Bufalin derivatives have a higher affinity with key targets. The cdocker interaction energy (CIE) of BF211, compound 1, and compound 2 with PI3K were -48.0722 kcal/mol, -50.8791 kcal/mol, and -59.7326 kcal/mol, respectively, which were significantly lower than Bufalin (-26.0859 kcal/mol). CONCLUSIONS Bufalin and its derivatives have significant anti-HCC activity and show good potential for drug development. Their mechanism of action involves a complex network of AMPK targets and PI3K/AKT/mTOR signaling pathways. In the future, specific inhibitors should be developed against these targets and pathways as a new therapeutic strategy for HCC. Among them, compounds 2, 7, and 8 have a higher affinity for potential targets than Bufalin and its other derivatives and have higher research value. In addition, α-pyrone is the key pharmacophore of Bufalin, and structural modification of the C3 position can significantly regulate its cytotoxicity and solubility. Therefore, optimization of the structure of the C3 position is expected to reduce the toxicity and improve the water solubility of Bufalin, overcoming the limitations of its clinical application and providing a safer and more effective solution for the treatment of HCC.
Collapse
Affiliation(s)
- Xinchen Gao
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Tianrun Bian
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xinyu Wei
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Mengsi Xu
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jiali Ren
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ying Zhao
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yanchao Zheng
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
| | - Xiankuan Li
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin 301617, China.
| |
Collapse
|
14
|
Chen ZJ, Wang XK, Han CY, He YF, Liang TY, Mo ST, Zhu GZ, Yang CK, Ye XP, Lv ZL, Pang SF, Chen XD, Wang P, Peng T. Diagnostic value of alpha-fetoprotein and prothrombin induced by vitamin K absence-II in serum, bile, and feces in hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:105311. [DOI: 10.4251/wjgo.v17.i5.105311] [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: 01/17/2025] [Revised: 03/06/2025] [Accepted: 03/18/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common pathological type of liver cancer and was the third leading cause of cancer-related deaths worldwide in 2020.
AIM To evaluate the diagnostic potential of key tumor markers in serum, bile, and fecal samples for detecting HCC.
METHODS Blood, bile, and fecal samples were collected from patients (n = 265) with HCC and cholecystitis from Guangxi Medical University’s First Affiliated Hospital. Immunohistochemistry was performed on 69 HCC samples, and 16S ribosomal RNA sequencing was conducted on 166 fecal samples. Tumor marker cut-off values in bile and feces were determined using the Youden index, while serum biomarkers followed hospital standards. Diagnostic performance was evaluated using receiver operating characteristic analysis.
RESULTS The areas under the curve (AUCs) for distinguishing HCC were 0.898, 0.904, and 0.859 for serum alpha-fetoprotein (AFP), prothrombin induced by vitamin K absence-II (PIVKA-II), and bile AFP, respectively. Serum AFP had the highest diagnostic value (80%) for early-stage HCC. Combination analysis found that bile AFP and serum PIVKA-II achieved the highest AUC of 0.965 (P < 0.001), suggesting that bile AFP may serve as a valuable complementary biomarker, particularly in cases where serum AFP is not significantly elevated. Additionally, bile AFP was positively correlated with Actinomyces, which plays a significant role in promoting tumorigenesis; and was negatively correlated with Faecalibacterium, which was associated with robust anticancer immune responses (P < 0.05). These findings suggest the potential role of gut microbiota in modulating AFP levels and HCC progression.
CONCLUSION Bile AFP improved the sensitivity of HCC detection, with the combination of bile AFP and PIVKA-II demonstrating the highest AUC for HCC diagnosis. AFP is associated with poorer clinical outcomes.
Collapse
Affiliation(s)
- Zi-Jun Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiang-Kun Wang
- Departments of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Chuang-Ye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yong-Fei He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tian-Yi Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shu-Tian Mo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xin-Ping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zi-Li Lv
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shi-Fu Pang
- AIage Life Science Corporation Ltd., Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Dong Chen
- AIage Life Science Corporation Ltd., Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Peng Wang
- Department of Health Management and Division of Physical Examination, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| |
Collapse
|
15
|
Chung SW, Kim JS, Choi WM, Choi J, Lee D, Shim JH, Lim YS, Lee HC, Kim KM. Synergistic Effects of Transarterial Chemoembolization and Lenvatinib on HIF-1α Ubiquitination and Prognosis Improvement in Hepatocellular Carcinoma. Clin Cancer Res 2025; 31:2046-2055. [PMID: 39992640 DOI: 10.1158/1078-0432.ccr-24-1228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 12/09/2024] [Accepted: 02/20/2025] [Indexed: 02/26/2025]
Abstract
PURPOSE A recent trial has shown that adding transarterial chemoembolization (TACE) to lenvatinib therapy results in enhanced therapeutic efficacy in hepatocellular carcinoma (HCC). We aimed to assess the effectiveness of the lenvatinib and TACE combination in a real-world clinical context for managing HCC and to elucidate the molecular pathways involved. EXPERIMENTAL DESIGN This retrospective analysis included 199 patients diagnosed with HCC and having intrahepatic lesions between 2018 and 2021. The cohort was divided into those who received lenvatinib plus TACE (n = 62, combination group) and those who received lenvatinib monotherapy (n = 137, monotherapy group). To further explore the underlying mechanisms, Huh-7 cells were exposed to lenvatinib or a vehicle for 48 hours under normoxic or hypoxic conditions. RESULTS Propensity score-matched analysis revealed a significant improvement in both overall survival (adjusted HR, 0.38; 95% confidence interval, 0.24-0.59; P < 0.001) and progression-free survival (adjusted HR, 0.41; 95% confidence interval, 0.26-0.64; P < 0.001) in the combination group compared with the monotherapy group. In laboratory experiments, under hypoxic conditions, lenvatinib notably attenuated hypoxia-inducible factor-1α (HIF-1α) protein levels in Huh-7 cells without altering its mRNA levels. Intriguingly, lenvatinib facilitated the mouse double minute 2 homolog-mediated ubiquitination and subsequent degradation of HIF-1α. Additionally, cell viability assays confirmed a significant decrease in Huh-7 cell survival following lenvatinib treatment under hypoxic conditions. CONCLUSIONS The combination of lenvatinib and TACE significantly improved survival in patients with HCC. The mechanistic foundation seems to be the lenvatinib-triggered degradation of HIF-1α via the mouse double minute 2 homolog-dependent ubiquitination pathway, highlighting a potential therapeutic target in HCC treatment.
Collapse
Affiliation(s)
- Sung Won Chung
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jin Sun Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Danbi Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| |
Collapse
|
16
|
Rafaqat S, Noshair I, Shahid M, Bibi S, Hafeez R, Hamid H. Correlation between prognostic markers and clinical parameters in hepatocellular carcinoma: Pathophysiological aspects to therapeutic targets. World J Gastrointest Oncol 2025; 17:106278. [DOI: 10.4251/wjgo.v17.i5.106278] [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: 02/20/2025] [Revised: 03/08/2025] [Accepted: 03/17/2025] [Indexed: 05/15/2025] Open
Abstract
One of the main causes of cancer-related morbidity and mortality globally is hepatocellular carcinoma (HCC). At every stage of the disease, HCC may now be treated using a variety of therapy techniques. Nevertheless, despite the abundance of effective therapeutic choices, the prognosis for patients with HCC is still typically dismal. Prognostic indicators are crucial when assessing prognosis and tracking tumor metastases or recurrence. There are many prognostic markers in HCC. We mainly focused on newly reported prognostic markers such as MEX3A, apolipoprotein B, alpha-fetoprotein, circulating tumor cells, SAMD13, Agrin, and Glypican-3 in the pathogenesis of HCC. Further, we highlighted how these prognostic markers correlated to clinical parameters such as tumor node metastasis, tumor diameter, differentiation, hepatocirrhosis, vascular invasion, and others in HCC. Therefore, identifying specific prognostic biomarkers of HCC helps to provide a great opportunity to improve the prognosis in patients with HCC and provide therapeutic targets.
Collapse
Affiliation(s)
- Saira Rafaqat
- Department of Zoology, Lahore College for Women University, Lahore 54000, Pakistan
| | - Iqra Noshair
- Department of Zoology, Lahore College for Women University, Lahore 54000, Pakistan
| | - Momina Shahid
- Department of Zoology, University of Narowal, Narowal 54000, Pakistan
| | - Sadaf Bibi
- Department of Zoology, Government College University, Lahore 54000, Pakistan
| | - Ramsha Hafeez
- Department of Zoology, Lahore College for Women University, Lahore 54000, Pakistan
| | - Hafsa Hamid
- Department of Biotechnology, Lahore College for Women University, Lahore 54000, Pakistan
| |
Collapse
|
17
|
Terzapulo X, Dyussupova A, Ilyas A, Boranova A, Shevchenko Y, Mergenbayeva S, Filchakova O, Gaipov A, Bukasov R. Detection of Cancer Biomarkers: Review of Methods and Applications Reported from Analytical Perspective. Crit Rev Anal Chem 2025:1-46. [PMID: 40367278 DOI: 10.1080/10408347.2025.2497868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
One in five deaths in developed countries is related to cancer. The cancer prevalence is likely to grow with aging population. The affordable and accurate early diagnostics of cancer based on detection of cancer biomarkers at low concentration during its early stages is one of the most efficient way to decrease mortality and human suffering from cancer. The data from 201 analytical papers are tabulated in 9 tables, illustrated in 8 figures and used for comparative analysis of methods applied for cancer biomarker detection, including polymerase chain reaction, Loop-mediated isothermal amplification (LAMP), mass spectrometry, enzyme-linked immunosorbent assay, electroanalytical methods, immunoassays, surface enhanced Raman scattering, Fourier Transform Infrared and others in terms of above-mentioned performance parameters. Median and/or average limit of detection (LOD) are calculated and compared between different analytical methods. We also described and compared LOD of the methods used for detection of three frequently detected cancer biomarkers: carcinoembryonic antigen, prostate-specific antigen and alpha-fetoprotein. Among those methods of detection, the reported electrochemical sensors often demonstrate relatively high sensitivity/low LOD while they often have a moderate instrumental cost and fast time to results. The review tabulates, compares and discusses analytical papers, which report LOD of cancer biomarkers and comprehensive quantitative comparison of various analytical methods is made. The discussion of those techniques applied for cancer biomarker detection included brief summary of pro and cons for each of those methods.
Collapse
Affiliation(s)
- Xeniya Terzapulo
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Aigerim Dyussupova
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Aisha Ilyas
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Aigerim Boranova
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Yegor Shevchenko
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Saule Mergenbayeva
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Olena Filchakova
- Biology Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| | - Abduzhappar Gaipov
- Department of Medicine, Nazarbayev University School of Medicine, Astana, Republic of Kazakhstan
| | - Rostislav Bukasov
- Chemistry Department, School of Sciences and Humanities, Nazarbayev University, Astana, Republic of Kazakhstan
| |
Collapse
|
18
|
Zhang H, Pan X, Wu Q, Wu Y, Zheng N, Ning S, Zeng D, Chen L, Li W, Wang J, Jiang T, Long X, Watabe H, Wu H, Wu Y, Wei Y, Yin X. Synthesis and characterization of functional chitosan-based microspheres as biodegradable yttrium-90 delivery system for radioembolization therapy. Int J Biol Macromol 2025:144090. [PMID: 40360115 DOI: 10.1016/j.ijbiomac.2025.144090] [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: 11/20/2024] [Revised: 01/02/2025] [Accepted: 05/08/2025] [Indexed: 05/15/2025]
Abstract
Transarterial radioembolization (TARE) using yttrium-90 (90Y)-labeled glass and resin microspheres is an emerging therapeutic technique for hepatocellular carcinoma (HCC). However, the non-biodegradability and rapid settlement of current commercial microspheres might hinder their even distribution and repetitive administration thus causing unsatisfactory therapeutic effects. In this context, novel functional chitosan-based microspheres (CPIs) that can efficiently label Y as a favorable TARE material were developed for the first time by successive grafting poly (glycidyl methacrylate) (PGMA) and iminodiacetic acid (IDA) onto chitosan microspheres (CMs). The results confirmed that the CPIs had desirable spherical shapes with average diameters of around 20.9 μm, an ideal settlement rate within 5 min, and considerable biodegradability at 10th weeks. It reached Y adsorption equilibrium within 30 min and maintained the maximum adsorption capacity up to 14.95 mg g-1 at pH 6.0 following pseudo-second-order kinetic and Langmuir models. Additionally, Y-labeled CPIs were rather stable in vitro, for which Y would firmly interact with the sodium carboxylate group and tertiary amine nitrogen atoms on IDA, and its leakage when shaken in phosphate-buffered saline for 24 h was barely detected. Altogether, these properties of the as-developed CPIs hold great potential as promising radioembolization microspheres for TARE therapy against liver cancer.
Collapse
Affiliation(s)
- Haoyu Zhang
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Xiangni Pan
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Qiang Wu
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Yehuizi Wu
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Ningchao Zheng
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Shunyan Ning
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Deqian Zeng
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Lifeng Chen
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Wenlong Li
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Ji Wang
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Tianjiao Jiang
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China
| | - Xizhi Long
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Hiroshi Watabe
- Division of Radiation Protection and Safety Control, Cyclotron and Radioisotope Center, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan
| | - Hao Wu
- School of Nuclear Science and Engineering, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China
| | - Yan Wu
- School of Nuclear Science and Engineering, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China
| | - Yuezhou Wei
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China; School of Nuclear Science and Engineering, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China
| | - Xiangbiao Yin
- School of Nuclear Science and Technology, University of South China, 28 Changsheng West Road, Hengyang 421001, China; Key Laboratory of Advanced Nuclear Energy Design and Safety, Ministry of Education, University of South China, 28 Changsheng West Road, Hengyang, China.
| |
Collapse
|
19
|
Luo J, Wan X, Du J, Liu L, Zhao L, Peng X, Wu M, Huang S, Nie X. Comprehensive multi-phase 3D contrast-enhanced CT imaging for primary liver cancer. Sci Data 2025; 12:768. [PMID: 40348741 PMCID: PMC12065907 DOI: 10.1038/s41597-025-05125-2] [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: 08/28/2024] [Accepted: 05/01/2025] [Indexed: 05/14/2025] Open
Abstract
Primary liver cancer is a significant global health issue with high incidence and mortality rates worldwide. Accurate diagnosis and classification of its subtypes are crucial for choosing the right treatment options and improving patient outcomes. Contrast-enhanced computed tomography (CECT) is known for its high sensitivity and specificity in diagnosing liver cancer. However, publicly available datasets of liver cancer CECT scans are limited and often do not fully cover all subtypes or include complete CT scan phases. We hypothesize that using 3D CECT images with complete scan phases can help develop and validate diagnostic and segmentation models for primary liver cancer. Therefore, we created a CECT dataset with annotated liver and lesion areas. This dataset includes 278 cases of liver cancer, featuring hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma, along with CECT images from 83 non-liver cancer subjects. It contains over 50,000 layers of liver cancer lesion images. We believe this dataset can offer valuable support for developing and validating models for classifying and segmenting primary liver cancer.
Collapse
Affiliation(s)
- Jiawei Luo
- West China Biomedical Big Data Center, West China Hospital; Med-X Center for Informatics, Sichuan University, Chengdu, 610044, China
| | - Xiaoyu Wan
- School of Communications and Information Engineering, Chongqing University of Posts and Telecommunications, Chongqing, 400065, China
| | - Jinchao Du
- Department of Radiology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400000, China
| | - Li Liu
- Department of Radiology, The People's Hospital of Yubei District of Chongqing city, Chongqing, 401120, China
| | - Ling Zhao
- Department of Radiology, The People's Hospital of Yubei District of Chongqing city, Chongqing, 401120, China
| | - Xin Peng
- Department of Radiology, The People's Hospital of Yubei District of Chongqing city, Chongqing, 401120, China
| | - Min Wu
- College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, China
| | - Shixin Huang
- Department of Scientific Research, The People's Hospital of Yubei District of Chongqing city, Chongqing, 401120, China.
| | - Xixi Nie
- School of Computer Science and Technology, Chongqing University of Posts and Telecommunications, Chongqing, 400065, China.
| |
Collapse
|
20
|
Kuo CL, Yen RF, Wu YM, Wang MH. Phase I Study of 68Ga-NOTA-HL for PET/CT Imaging of Hepatic Asialoglycoprotein Receptors in Healthy Volunteers. J Nucl Med Technol 2025:jnmt.124.268430. [PMID: 40345823 DOI: 10.2967/jnmt.124.268430] [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: 07/15/2024] [Accepted: 02/26/2025] [Indexed: 05/11/2025] Open
Abstract
This study investigated the safety, biodistribution, and dosimetry of 68Ga-hexavalent lactoside (68Ga-NOTA-HL), a PET tracer targeting asialoglycoprotein receptors (ASGPRs) on hepatocytes. ASGPRs, key for glycoprotein homeostasis, serve as a valuable biomarker of liver function. 68Ga-NOTA-HL demonstrated excellent safety in 12 healthy volunteers with no adverse events. Biodistribution studies revealed high liver uptake with minimal uptake in other organs, consistent with ASGPR targeting. The effective dose was 0.0289 mSv/MBq, indicating low radiation exposure. These findings suggest 68Ga-NOTA-HL PET/CT holds significant promise as a safe and effective imaging technique for assessing liver function. The high liver specificity and extremely low background activity provide a strong foundation for further clinical investigations into its potential for evaluating liver function in various clinical settings, including the assessment of liver reserve in patients with liver diseases.
Collapse
Affiliation(s)
| | | | - Yao-Ming Wu
- National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Hui Wang
- National Atomic Research Institute, Taoyuan, Taiwan; and
| |
Collapse
|
21
|
Xu J, Luo X, Su W, Jia G, Cai H, Li D, Li R, Wang X, Yang Y, Wang T, Zuo C. Turning Waste into Treasure: Radiation Byproduct-Induced Fe(III)/Fe(II) Conversion for Efficient Ferroptosis to Improve Iodine-131-Based Transarterial Radioembolization for Liver Tumors. ACS APPLIED MATERIALS & INTERFACES 2025. [PMID: 40338615 DOI: 10.1021/acsami.5c01445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Transarterial radioembolization (TARE) is a primary palliative treatment for advanced liver cancer. Nonetheless, its therapeutic efficacy is frequently hindered by resistance to tumor cell apoptosis induced by inter-radiotherapy. Induction of multiple cell death modalities provides a potential solution to this challenge. Ferroptosis, a distinct form of cell death from apoptosis, is dependent on the intracellular Fe2+-mediated Fenton reaction for the production of hydroxyl radicals (·OH) and is gaining recognition as a promising approach for cancer treatment. In this study, we synthesized a therapeutic radionuclide iodine-131 (131I)-based TARE agent by combining 131I-labeled iron-based MIL-88B(Fe) nanoparticles (NPs) (abbreviated as 131I-MIL-88B(Fe)) with Lipiodol to achieve a combined apoptosis-ferroptosis tumor therapy. Specifically, a mixture of Lipiodol and 131I-MIL-88B(Fe) NPs was injected into the liver tumors through the hepatic artery. Lipiodol blocks the arterial blood supply of the tumor, causing tumor tissue necrosis, whereas 131I inter-radiotherapy damages deoxyribonucleic acid (DNA) through direct action or indirectly via the production of ·OH through H2O radiolysis, leading to tumor cell apoptosis. Importantly, hydrated electrons (eaq-), a byproduct of H2O radiolysis, promoted the conversion of Fe3+ to Fe2+ in MIL-88B(Fe) NPs, enhancing the efficacy of the Fenton reaction and triggering ferroptosis. In vitro experiments demonstrated that compared to 131I alone, 131I-MIL-88B(Fe) NPs significantly enhanced ferroptosis-mediated tumor cell death due to 131I-induced Fe2+ production, which increased catalytic activity in the Fenton reaction. In a rat model bearing orthotopic N1S1 liver tumors, TARE with Lipiodol and 131I-MIL-88B(Fe) NPs induced tumor cell necrosis, apoptosis, and ferroptosis, resulting in improved therapeutic outcomes. This study leverages eaq- to facilitate Fe3+/Fe2+ conversion for efficient ferroptosis, turning waste into a valuable resource. This demonstrated the innovative integration of multiple treatment strategies to augment the efficacy of TARE in liver cancer therapy.
Collapse
Affiliation(s)
- Jiangnan Xu
- School of Medical Imaging, Xuzhou Medical University, Xuzhou 221004, China
- Department of Nuclear Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Xiu Luo
- Department of Nuclear Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Weiwei Su
- Department of Nuclear Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
- Department of Radiology, Naval Medical Centre, Shanghai 200052, China
| | - Guorong Jia
- Department of Nuclear Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Huawei Cai
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Danni Li
- Department of Nuclear Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Rou Li
- Department of Nuclear Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Xiangdong Wang
- Mini-Invasive Intervention Center, the Third Affiliated Hospital of Naval Medical University, Shanghai 200438, China
| | - Yefa Yang
- Mini-Invasive Intervention Center, the Third Affiliated Hospital of Naval Medical University, Shanghai 200438, China
| | - Tao Wang
- Department of Nuclear Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Changjing Zuo
- School of Medical Imaging, Xuzhou Medical University, Xuzhou 221004, China
- Department of Nuclear Medicine, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| |
Collapse
|
22
|
Taha S, Aljishi M, Sultan A, Bakhiet M. Calcium Homeostasis Disrupted-How Store-Operated Calcium Entry Factor SARAF Silencing Impacts HepG2 Liver Cancer Cells. Int J Mol Sci 2025; 26:4426. [PMID: 40362663 DOI: 10.3390/ijms26094426] [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: 03/15/2025] [Revised: 04/14/2025] [Accepted: 04/14/2025] [Indexed: 05/15/2025] Open
Abstract
Hepatocellular carcinoma (HCC), a highly aggressive liver malignancy, is often associated with disrupted calcium homeostasis. Store-operated calcium entry (SOCE), involving components such as STIM1, Orai1, and SARAF, plays a critical role in calcium signaling and cancer progression. While STIM1 and Orai1 have been extensively studied, SARAF's role as a negative regulator of SOCE in HCC remains poorly understood. This preliminary study investigated SARAF's effects on calcium homeostasis, proliferation, and migration in HepG2 liver cancer cells, providing initial evidence of its tumor-suppressive role. SARAF expression was modulated using siRNA knockdown and overexpression plasmids, with validation by qRT-PCR. Functional assays demonstrated that SARAF silencing increased proliferation by 50% and migration by 40% (p < 0.05), while SARAF overexpression reduced proliferation by 50% and migration by 45% (p < 0.01), highlighting its tumor-suppressive role. Intracellular calcium levels, elevated in HepG2 cells, were partially restored by SARAF overexpression, though SARAF silencing did not further disrupt calcium regulation. These findings suggest that SARAF negatively regulates proliferation and migration in HCC, potentially through its role in maintaining calcium homeostasis. SARAF represents a promising therapeutic target in HCC. Future studies should explore the downstream molecular mechanisms governing SARAF's effects, investigate its role in other cancers, and assess its clinical potential for liver cancer therapy.
Collapse
Affiliation(s)
- Safa Taha
- Princess Al Jawhara Center for Molecular Medicine, Genetics and Inherited Diseases, Department of Molecular Medicine, College of Medicine and Health Sciences, Arabian Gulf University, Manama P.O. Box 26671, Bahrain
| | - Muna Aljishi
- Princess Al Jawhara Center for Molecular Medicine, Genetics and Inherited Diseases, Department of Molecular Medicine, College of Medicine and Health Sciences, Arabian Gulf University, Manama P.O. Box 26671, Bahrain
| | - Ameera Sultan
- Princess Al Jawhara Center for Molecular Medicine, Genetics and Inherited Diseases, Department of Molecular Medicine, College of Medicine and Health Sciences, Arabian Gulf University, Manama P.O. Box 26671, Bahrain
| | - Moiz Bakhiet
- Princess Al Jawhara Center for Molecular Medicine, Genetics and Inherited Diseases, Department of Molecular Medicine, College of Medicine and Health Sciences, Arabian Gulf University, Manama P.O. Box 26671, Bahrain
| |
Collapse
|
23
|
Liu C, Li M, Liu L, Xu Q, Zheng L, Wu C, Ren J, Zhang T, Wang H, Lin Z. TGF-β1 induces autophagy and mediates the effect on macrophages differentiation in primary liver cancer. Int Immunopharmacol 2025; 157:114799. [PMID: 40339499 DOI: 10.1016/j.intimp.2025.114799] [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: 02/04/2025] [Revised: 05/01/2025] [Accepted: 05/01/2025] [Indexed: 05/10/2025]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are closely associated with tumor development and patient outcomes due to their plasticity and polarization capacity. Several distinct TAMs have been proposed, but a complete understanding of heterogeneity and differentiation spectrum of macrophage in human primary liver cancer remains elusive. METHODS Deep single-cell RNA sequencing (scRNA-seq) data from 19 primary liver cancer patients were used to profile the transcriptomes of TAMs in liver cancer. Ingenuity pathway analysis (IPA) and in vitro experiments were used to explore possible mechanisms responsible for related signaling pathways altered at the transcriptional level. Finally, we analyzed the relationship between the abundance of the TAMs and the survival outcomes of the 428 patients in the Cancer Genome Atlas (TCGA). RESULTS Transcriptional profiles allowed us to identify four distinct TAMs cell subsets based on molecular and functional properties and to reconstruct their developmental trajectory. Specifically, TAM_c4 was preferentially enriched and potentially expanded in the advanced-stage patients or those receiving immune checkpoint blockade therapy (ICT). Gene pathway analysis revealed aberrant TGFB1 activation in TAM_c4, which was experimentally confirmed to drive TAM phenotypic transitions via autophagy signaling. High abundance of TAM_c4 is found to be related to a short survival time and low abundance of CD8+ T cells in primary liver cancers. CONCLUSIONS This integrated transcriptome compendium and experimental validation offer both mechanistic insights and a resource for understanding TAM heterogeneity in primary liver cancers.
Collapse
Affiliation(s)
- Chao Liu
- Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang, People's Republic of China
| | - Mingjie Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Lichao Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Qian Xu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Linlin Zheng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Cailing Wu
- Faculty of Medicine, JiuJiang University, Jiujiang, People's Republic of China
| | - Jinghua Ren
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, People's Republic of China
| | - Tao Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
| | - Haihong Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
| | - Zhenyu Lin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
| |
Collapse
|
24
|
Yau T, Galle PR, Decaens T, Sangro B, Qin S, da Fonseca LG, Karachiwala H, Blanc JF, Park JW, Gane E, Pinter M, Peña AM, Ikeda M, Tai D, Santoro A, Pizarro G, Chiu CF, Schenker M, He A, Chon HJ, Wojcik-Tomaszewska J, Verset G, Wang QQ, Stromko C, Neely J, Singh P, Jimenez Exposito MJ, Kudo M. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet 2025:S0140-6736(25)00403-9. [PMID: 40349714 DOI: 10.1016/s0140-6736(25)00403-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/21/2025] [Accepted: 02/26/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Patients with unresectable hepatocellular carcinoma have a poor prognosis, and treatments with long-term benefits are needed. We report results from the preplanned interim analysis of the CheckMate 9DW trial assessing nivolumab plus ipilimumab versus lenvatinib or sorafenib for unresectable hepatocellular carcinoma in the first-line setting. METHODS This open-label, randomised, phase 3 trial enrolled patients aged 18 years or older with unresectable hepatocellular carcinoma without previous systemic therapy at 163 hospitals and cancer centres across 25 countries in Asia, Australia, Europe, North America, and South America. Patients had at least one measurable untreated lesion per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, a Child-Pugh score of 5 or 6, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive response technology system to receive nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) intravenously every 3 weeks for up to four doses, followed by nivolumab 480 mg every 4 weeks or investigator's choice of either oral lenvatinib (8 mg or 12 mg mg daily depending on bodyweight) or oral sorafenib (400 mg twice daily). Randomisation was stratified by aetiology; the presence of macrovascular invasion, extrahepatic spread, or both; and baseline alpha-fetoprotein concentration. The primary endpoint was overall survival, which was assessed in all randomly assigned patients; safety was an exploratory endpoint and was assessed in all randomly assigned patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04039607 (ongoing). FINDINGS Between Jan 6, 2020, and Nov 8, 2021, 668 patients were randomly assigned to nivolumab plus ipilimumab (n=335) or lenvatinib or sorafenib (n=333). Early crossing of the overall survival Kaplan-Meier curves reflected a higher number of deaths during the first 6 months after randomisation with nivolumab plus ipilimumab (hazard ratio 1·65 [95% CI 1·12-2·43]) but was followed by a sustained separation of the curves thereafter in favour of nivolumab plus ipilimumab (0·61 [0·48-0·77]). After a median follow-up of 35·2 months (IQR 31·1-39·9), overall survival was significantly improved with nivolumab plus ipilimumab versus lenvatinib or sorafenib (median 23·7 months [95% CI 18·8-29·4] vs 20·6 months [17·5-22·5]; hazard ratio 0·79 [0·65-0·96]; two-sided stratified log-rank p=0·018); respective overall survival rates were 49% (95% CI 44-55) versus 39% (34-45) at 24 months and 38% (32-43) versus 24% (19-30) at 36 months. Overall, 137 (41%) of 332 patients receiving nivolumab plus ipilimumab and 138 (42%) of 325 patients receiving lenvatinib or sorafenib had grade 3-4 treatment-related adverse events. 12 deaths were attributed to treatment with nivolumab plus ipilimumab and three were attributed to treatment with lenvatinib or sorafenib. INTERPRETATION Nivolumab plus ipilimumab showed a significant overall survival benefit versus lenvatinib or sorafenib and manageable safety in patients with previously untreated unresectable hepatocellular carcinoma. These results support nivolumab plus ipilimumab as a first-line treatment in this setting. FUNDING Bristol Myers Squibb.
Collapse
Affiliation(s)
- Thomas Yau
- Centre of Cancer Medicine and University Department of Medicine, The University of Hong Kong, Hong Kong
| | - Peter R Galle
- University Medical Center, I Medical Department, Mainz, Germany.
| | - Thomas Decaens
- University of Grenoble Alpes, CHU Grenoble Alpes, Institute for Advanced Biosciences, CNRS UMR 5309-INSERM U1209, Grenoble, France
| | - Bruno Sangro
- Clinica Universidad de Navarra and CIBEREHD, Pamplona-Madrid, Spain
| | - Shukui Qin
- Nanjing Tianyinshan Hospital of China Pharmaceutical University, Nanjing, China
| | - Leonardo G da Fonseca
- Instituto do Cancer do Estado de São Paulo, ICESP, University of São Paulo School of Medicine, São Paulo, Brazil
| | | | | | - Joong-Won Park
- National Cancer Center and Myongji Hospital, Goyang, South Korea
| | - Edward Gane
- University of Auckland, Auckland, New Zealand
| | | | - Ana Matilla Peña
- Hospital General Universitario Gregorio Marañón, CIBEREHD, Madrid, Spain
| | - Masafumi Ikeda
- National Cancer Center Hospital East, Kashiwa Chiba, Japan
| | | | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, and IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | | | | | - Aiwu He
- MedStar Georgetown University Hospital, Washington, DC, USA
| | - Hong Jae Chon
- Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, South Korea
| | | | - Gontran Verset
- HUB-Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Qi Qi Wang
- Bristol Myers Squibb, Princeton, NJ, USA
| | | | | | | | | | | |
Collapse
|
25
|
Sun Y, Yang H, Li S, Zheng R, Liu B, Lin J, Huang F, Nong W, Luo L, Xie X, Huang G. An Accurate Model for Microvascular Invasion Prediction in Solitary Hepatocellular Carcinoma ≤5 cm Based on CEUS and EOB-MRI: A Retrospective Study with External Validation. Acad Radiol 2025:S1076-6332(25)00361-7. [PMID: 40335335 DOI: 10.1016/j.acra.2025.04.021] [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: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 05/09/2025]
Abstract
RATIONALE AND OBJECTIVES To develop a model combining contrast-enhanced ultrasound (CEUS) and ethoxybenzyl-enhanced magnetic resonance imaging (EOB-MRI) for predicting microvascular invasion (MVI) in solitary hepatocellular carcinoma (HCC) ≤5 cm. MATERIALS AND METHODS Patients between December 2019 and May 2024 in one center were retrospectively enrolled and randomly divided into the training cohort and internal validation cohort in a ratio of 7:3. Patients in a separate center were enrolled between January 2022 and December 2023 to be included as the external validation cohort. CEUS and EOB-MRI image features were extracted and used to develop models in the training cohort, and verified in the two validation cohorts. The predictive accuracy and clinical utility of models were evaluated using area under receiver operating characteristic curve (AUROC), Brier score, calibration plot and decision curve analysis (DCA). Net reclassification index (NRI) and integrated discrimination improvement (IDI) were used to compare different models. RESULTS From the two centers a total of 493 patients, of which 134 were MVI positive, were evaluated. The CEUS+EOB model included seven image features and showed better discrimination ability than the individual CEUS/EOB-MRI model, with AUROCs of 0.92, 0.94, and 0.90 in the training cohort and two validation cohorts, respectively (p<0.05). The lowest Brier score of the combined model indicated the highest predictive precision. DCA also showed that the combined model added more net benefits. Both the NRI and IDI values >0 indicated that the combined model had significantly positive improvement (p<0.05). CONCLUSION The CEUS+EOB model was developed to assist clinicians in evaluating MVI in solitary HCC ≤5 cm.
Collapse
Affiliation(s)
- Yueting Sun
- Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhong Shan Road, Guangzhou 510080, PR China (Y.S., R.Z., B.L., J.L., X.X., G.H.)
| | - Hong Yang
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, No. 6, Shuangyong Road, 530021 Nanning, PR China (H.Y.)
| | - Shurong Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhong Shan Road, Guangzhou 510080, PR China (S.L.)
| | - Ruiying Zheng
- Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhong Shan Road, Guangzhou 510080, PR China (Y.S., R.Z., B.L., J.L., X.X., G.H.)
| | - Baoxian Liu
- Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhong Shan Road, Guangzhou 510080, PR China (Y.S., R.Z., B.L., J.L., X.X., G.H.)
| | - Jinhua Lin
- Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhong Shan Road, Guangzhou 510080, PR China (Y.S., R.Z., B.L., J.L., X.X., G.H.)
| | - Fen Huang
- Department of Medical Ultrasonics, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-Sen University, Guangxi Zhuang Autonomous Region, No. 3, Foziling Road, 530021 Nanning, PR China (F.H., W.N., L.L., G.H.)
| | - Wanxian Nong
- Department of Medical Ultrasonics, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-Sen University, Guangxi Zhuang Autonomous Region, No. 3, Foziling Road, 530021 Nanning, PR China (F.H., W.N., L.L., G.H.)
| | - Lan Luo
- Department of Medical Ultrasonics, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-Sen University, Guangxi Zhuang Autonomous Region, No. 3, Foziling Road, 530021 Nanning, PR China (F.H., W.N., L.L., G.H.)
| | - Xiaoyan Xie
- Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhong Shan Road, Guangzhou 510080, PR China (Y.S., R.Z., B.L., J.L., X.X., G.H.)
| | - Guangliang Huang
- Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhong Shan Road, Guangzhou 510080, PR China (Y.S., R.Z., B.L., J.L., X.X., G.H.); Department of Medical Ultrasonics, Guangxi Hospital Division of the First Affiliated Hospital, Sun Yat-Sen University, Guangxi Zhuang Autonomous Region, No. 3, Foziling Road, 530021 Nanning, PR China (F.H., W.N., L.L., G.H.).
| |
Collapse
|
26
|
Xu X, Cheng Y, Yang Z, Yin Y, Qian Y, Yang H, Zhu S, Tian H, Zhuang Y, Zhu S, Yang P, Qin S, Shen W. Wogonin potentiates the irradiation effect on hepatocellular carcinoma by activating the Hippo-Yes-associated protein/transcriptional co-activator with PDZ-binding motif pathway. Int Immunopharmacol 2025; 157:114740. [PMID: 40318272 DOI: 10.1016/j.intimp.2025.114740] [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: 11/26/2024] [Revised: 04/11/2025] [Accepted: 04/23/2025] [Indexed: 05/07/2025]
Abstract
OBJECTIVE To investigate whether wogonin increases the radiosensitivity of hepatocellular carcinoma (HCC) cells by activating Hippo-Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling. METHODS HCC cells were treated with irradiation and wogonin; their proliferation and apoptosis were evaluated. Xenograft models were established to assess the radio-synergistic effects of wogonin; we evaluated whether wogonin influences the efficacy of radiotherapy in HCC cells by activating Hippo-YAP/TAZ signaling. RESULTS Fifty micromolar wogonin enhanced the radiosensitivity of HCC cells; 4-Gy X-rays promoted apoptosis in HCC cells. Wogonin pretreatment significantly increased radiosensitivity. In xenograft models, tumor weight and volume in the 100 mg/kg wogonin plus irradiation group were significantly reduced; pYAP and pTAZ levels were downregulated in HCC cells treated with radiotherapy. Following treatment with 4-Gy X-rays and 100 μM wogonin, the relative pYAP/total YAP and pTAZ/total TAZ ratios increased. We identified the possible target genes of YAP/TAZ: AXL, CCN1, and CCN2. WB results revealed the upregulation of AXL, CCN1, and CCN2 in the irradiation group. However, in the group receiving irradiation and wogonin, the protein expression levels of AXL, CCN1, and CCN2 were downregulated. XMU-MP-1 inhibited pYAP and pTAZ expression in the combination treatment group, thereby promoting AXL, CCN1, and CCN2 expression. The proliferative ability of HCC cells in the wogonin plus irradiation group was partially recovered following treatment with XMU-MP-1. Apoptosis in HCC cells was reversed after pretreatment with 2 μM XMU-MP-1 in the wogonin plus irradiation group. CONCLUSION Wogonin may modulate Hippo-YAP/TAZ signaling and enhance the radiosensitivity of HCCs.
Collapse
Affiliation(s)
- Xiao Xu
- Department of Radiotherapy, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China; Department of Radiotherapy, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China
| | - Yan Cheng
- School of Computer Science and Engineering, Taizhou Institute of Science & Technology, Taizhou 225300, Jiangsu, China
| | - Zeyu Yang
- Wisdom Lake Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou 215006, Jiangsu, China
| | - Yong Yin
- Department of Science and Technology, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Yonghong Qian
- Department of Radiotherapy, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Haiyu Yang
- Department of Clinical Laboratory, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Shusheng Zhu
- Department of Thoracic Surgery, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Hu Tian
- Department of Science and Technology, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Yanshuang Zhuang
- Department of Science and Technology, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Shimin Zhu
- Department of Radiotherapy, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Pingjin Yang
- Department of Clinical Laboratory, Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu, China
| | - Songbing Qin
- Department of Radiotherapy, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China.
| | - Weigan Shen
- Department of Cell Biology, Yangzhou University Medical College, Yangzhou 225100, Jiangsu, China.
| |
Collapse
|
27
|
Tee SR, Hughes H, Ryan ER, McCann J, O'Rourke C, Bourke M, MacNicholas R, Cantwell CP, Healy GM. Outcomes and Complications of Image-Guided Percutaneous Tumour Ablation for Hepatocellular Carcinoma at the Irish National Liver Transplant Centre. Can Assoc Radiol J 2025; 76:333-343. [PMID: 39344072 DOI: 10.1177/08465371241286795] [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] [Indexed: 10/01/2024] Open
Abstract
Background: Image-guided tumour ablation is a minimally invasive treatment for early stage hepatocellular carcinoma (HCC). Our study reviews the complications and long term outcomes in patients treated at a tertiary referral centre. Methods: Retrospective study. All patients with HCC who underwent microwave ablation (MWA) or radiofrequency ablation (RFA) from 1st January 2014 to 31st December 2022 were identified. Treatment response of target lesion, complications, and survival were recorded. Results: One hundred seventy ablations were performed in 118 patients; 70% MWA, 30% RFA. Median radiological follow-up 21 months (range 3-107). Follow-up imaging was reported using LI-RADS and mRECIST. At first follow-up imaging, 94 patients had complete response (primary efficacy rate 80.3%) while 19.7% (n = 23) had residual disease. Fifteen of these had repeat ablation; 10 had complete response (secondary efficacy rate 85.6%). By end of study duration, 70.5% (n = 79) achieved sustained local complete response from single ablation without documented recurrence. 14.3% (n = 16) required more than one ablation of target lesion. Overall, 84.8% (n = 95) demonstrated long term local complete response to ablation. Complication occurred in 5.9% (n = 10); 40.0% Grade I, 40.0% Grade II, 10.0% Grade III, 10.0% Grade IV as per the CIRSE Classification. 1-, 3-, and 5-year overall survival (OS) rate was 97%, 68%, and 61% respectively. Mean OS was 5.3 years (median 4.7). No difference in OS (P = .7) or local progression free survival (P = .5) between patients treated with MWA versus RFA. Conclusion: This study demonstrates excellent long-term response to TA, with acceptable complication profile. No difference in survival between RFA versus MWA.
Collapse
Affiliation(s)
- Syer Ree Tee
- Department of Radiology, St. Vincent's University Hospital, Dublin, Ireland
| | - Hannah Hughes
- Department of Radiology, St. Vincent's University Hospital, Dublin, Ireland
| | - Edmund Ronan Ryan
- Department of Radiology, St. Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Jeff McCann
- Department of Radiology, St. Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Colin O'Rourke
- Department of Radiology, St. Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Michele Bourke
- Department of Hepatology, St. Vincent's University Hospital, Dublin, Ireland
| | - Ross MacNicholas
- School of Medicine, University College Dublin, Dublin, Ireland
- Department of Hepatology, St. Vincent's University Hospital, Dublin, Ireland
| | - Colin P Cantwell
- Department of Radiology, St. Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Gerard M Healy
- Department of Radiology, St. Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| |
Collapse
|
28
|
Weiskirchen R, Weiskirchen S, Grassi C, Scaggiante B, Grassi M, Tierno D, Biasin A, Truong NH, Minh TD, Cemazar M, Pastorin G, Tonon F, Grassi G. Recent advances in optimizing siRNA delivery to hepatocellular carcinoma cells. Expert Opin Drug Deliv 2025; 22:729-745. [PMID: 40126051 DOI: 10.1080/17425247.2025.2484287] [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: 01/13/2025] [Accepted: 03/21/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Hepatocellularcarcinoma (HCC), the primary form of liver cancer, is the second leading cause of cancer-related deaths worldwide. Current therapies have limited effectiveness, particularly in advanced stages of the disease, highlighting the need for innovative treatment options. Small-interfering RNA(siRNA) molecules show great promise as a therapeutic solution since they can inhibit the expression of genes promoting HCC growth. Their cost-effective synthesis has further encouraged their potential use as novel drugs. However, siRNAs are vulnerable to degradation in biological environments, necessitating protective delivery systems. Additionally, targeted delivery to HCC is critical for optimal efficacy and minimal undesired side effects. AREACOVERED This review addresses the challenges associated with the delivery of siRNA toHCC, discussing and focusing on delivery systems based on lipid and polymeric nanoparticles in publications from the past five years. EXPERT OPINION Future nano particles will need to effectively cross the vessel wall, migrate through the extracellular matrix and finally cross the HCC cell membrane. This may be achieved by optimizing nanoparticle size, the equipment of nanoparticles withHCC targeting moieties and loading nanoparticles with siRNAs againstHCC-specific oncogenes.
Collapse
Affiliation(s)
- Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Sabine Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | | | | | - Mario Grassi
- Department of Engineering and Architecture, Trieste University, Trieste, Italy
| | - Domenico Tierno
- Clinical Department of Medical, Surgical and Health Sciences, Cattinara University Hospital, Trieste Univer-sity, Trieste, Italy
| | - Alice Biasin
- Department of Engineering and Architecture, Trieste University, Trieste, Italy
- Clinical Department of Medical, Surgical and Health Sciences, Cattinara University Hospital, Trieste Univer-sity, Trieste, Italy
| | - Nhung Hai Truong
- Laboratory of Regenerative Biomedicine, University of Science-VNUHCM, Ho Chi MInh City, Vietnam
- Faculty of Biology and Biotechnology, Viet Nam National University, Ho Chi Minh City, Vietnam
| | - Thanh Dang Minh
- Laboratory of Regenerative Biomedicine, University of Science-VNUHCM, Ho Chi MInh City, Vietnam
- Faculty of Biology and Biotechnology, Viet Nam National University, Ho Chi Minh City, Vietnam
| | - Maja Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Health Sciences, University of Primorska, Izola, Slovenia
| | - Giorgia Pastorin
- Pharmacy Department, National University of Singapore, Singapore
| | - Federica Tonon
- Clinical Department of Medical, Surgical and Health Sciences, Cattinara University Hospital, Trieste Univer-sity, Trieste, Italy
| | - Gabriele Grassi
- Clinical Department of Medical, Surgical and Health Sciences, Cattinara University Hospital, Trieste Univer-sity, Trieste, Italy
| |
Collapse
|
29
|
Ni W, Zhang M, Mo Y, Du W, Liu H, Wang Z, Cui Y, Zhang H, Wang Z, Liu L, Guo H, Niu R, Zhang F, Tian R. Macrophage membrane-based biomimetic nanocarrier system for enhanced immune activation and combination therapy in liver cancer. Drug Deliv Transl Res 2025; 15:1540-1553. [PMID: 39172178 DOI: 10.1007/s13346-024-01690-y] [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] [Accepted: 07/28/2024] [Indexed: 08/23/2024]
Abstract
Previous studies have demonstrated that the combination of photodynamic therapy, photothermal therapy and chemotherapy is highly effective in treating hepatocellular carcinoma (HCC). However, the clinical application of this approach has been hindered by the lack of efficient and low-toxicity drug delivery platforms. To address this issue, we developed a novel biomimetic nanocarrier platform named ZID@RM, which utilizes ZIF8 functional nanoparticles encapsulated with macrophage membrane and loaded with indocyanine green and doxorubicin. The bionic nanocarrier platform has good biocompatibility, reducing the risk of rapid clearance by macrophages and improving the targeting ability for HCC cells. Under the dual regulation of acidity and infrared light, ZID@RM stimulated the generation of abundant reactive oxygen species within HCC cells, induced tumor cell pyroptosis and promoted the release of damage-associated molecular patterns to induce immune responses. In the future, this technology platform has the potential to provide personalized and improved healthcare by using patients' own macrophage membranes to create an efficient drug delivery system for tumor therapy.Graphical abstract Scheme 1 Schematic representation of the synthesis of a biomimetic nanomedicine delivery platform (ZID@RM) and its application in tumor imaging-guided combination therapy.
Collapse
Affiliation(s)
- Wei Ni
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Mingzhu Zhang
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yueni Mo
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Wei Du
- Department of Immunology, Biochemistry and Molecular Biology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China
| | - Hui Liu
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Zhaosong Wang
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Yanfen Cui
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - He Zhang
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Zhiyong Wang
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Liming Liu
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Hui Guo
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Ruifang Niu
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Fei Zhang
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| | - Ran Tian
- Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
- Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| |
Collapse
|
30
|
Yang T, Yin DX, Diao YK, Wang MD, Wang XM, Zeng YY, Chen Z, Liu H, Chen FJ, Li YC, Xu JH, Wu H, Yao LQ, Xu XF, Li C, Gu LH, Chieh Kow AW, Pawlik TM, Shen F. Prognostic Value of the ASAP Score for Patients Undergoing Hepatic Resection for Hepatocellular Carcinoma: A Multicenter Analysis of 1,239 Patients. J Clin Exp Hepatol 2025; 15:102497. [PMID: 39917418 PMCID: PMC11795555 DOI: 10.1016/j.jceh.2024.102497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 12/23/2024] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND AND AIMS The ASAP score, which incorporates age, sex, alpha-fetoprotein (AFP), and protein induced by vitamin K absence-II, has demonstrated promise for early detection of hepatocellular carcinoma (HCC). However, its prognostic value after HCC treatment remains unknown. The current study sought to evaluate the prognostic value of the ASAP score to predict recurrence and survival following curative hepatic resection for HCC. METHODS This study using prospectively collected data included HCC patients who underwent curative-intent hepatic resection. The ASAP score was calculated preoperatively, and X-tile analysis was used to determine the optimal cutoff value. Univariate and multivariate analyses were performed to identify independent risk factors associated with recurrence and overall survival (OS). RESULTS Among 1239 patients in the analytic cohort, the optimal ASAP score cutoff was 4.8; patients were divided into low (n = 749) and high (n = 490) ASAP score subgroups. Patients with high ASAP scores had a higher incidence of 5-year recurrence (73.9% vs 51.0%, P < 0.001) and worse OS (31.7% vs 60.1%, P < 0.001) versus individuals with low scores. Multivariate analysis identified ASAP score ≥4.8 as an independent risk factor of both recurrence (hazard ratio [HR] 1.976, 95% confidence interval [CI]: 1.633-2.390, P < 0.001) and OS (HR 1.407, 95% CI 1.170-1.691, P < 0.001) after controlling for established clinicopathological factors. CONCLUSION Preoperative ASAP score was independently associated with recurrence and survival after HCC resection. The clinical utility of the ASAP score may be applicable to both diagnosis and prognosis, potentially improving postoperative surveillance and management strategies for HCC patients.
Collapse
Affiliation(s)
- Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Dong-Xu Yin
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yong-Kang Diao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Xian-Ming Wang
- Department of General Surgery, First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Zhong Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Han Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Fu-Jie Chen
- Department of Graduate, Bengbu Medical University, Bengbu, Anhui, China
| | - Yu-Chen Li
- Department of Graduate, Bengbu Medical University, Bengbu, Anhui, China
| | - Jia-Hao Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Lan-Qing Yao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Xin-Fei Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Li-Hui Gu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Alfred W. Chieh Kow
- Division of Hepatopancreaticobiliary Surgery and Liver Transplantation, Department of Surgery, National University Health System Singapore, Singapore
| | - Timothy M. Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH, United States
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| |
Collapse
|
31
|
Hsieh MC, Ratnapradipa KL, Rozek L, Wen S, Chiu YW, Peters ES. Temporal trends and patterns for early- and late-onset adult liver cancer incidence vary by race/ethnicity, subsite, and histologic type in the United States from 2000 to 2019. Cancer Causes Control 2025; 36:551-560. [PMID: 39786651 PMCID: PMC11982089 DOI: 10.1007/s10552-024-01955-4] [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: 08/17/2024] [Accepted: 12/20/2024] [Indexed: 01/12/2025]
Abstract
PURPOSE To examine incidence trends and patterns for early- and late-onset liver cancer. METHODS Liver and intrahepatic bile duct (IBD) cancers diagnosed between 2000 and 2019 were acquired from 22 SEER registries. Variables included early-onset (20-49) vs. late-onset (50+), anatomic subsite, histologic type (hepatocellular carcinoma [HCC] and IBD cholangiocarcinoma [ICC]), sex, and race/ethnicity. Age-standardized incidence rates were calculated using SEER*Stat. Jointpoint regression analysis was employed to estimate the annual percent change (APC) and the average APC (AAPC) with pairwise comparisons for trend by sex and by race/ethnicity stratified by age and subsite. RESULTS Liver cancer incidence decreased among early-onset (AAPC [95% CI] - 2.39 [- 2.74, - 2.07]) but increased among late-onset patients (2.85 [2.71, 3.01]), primarily driven by HCC (3.60 [3.50, 3.71]). IBD incidence increased for both ages with ICC incidence annually increasing 7.92% (6.84, 9.26) for early-onset and 6.32% (5.46, 8.86) for late-onset patients. Early-onset liver cancer displayed comparable trends across racial/ethnic groups; however, late-onset liver cancer showed more variation, particularly among American Indian/Alaska Native/Asian Pacific Islander (AI/AN/API) populations, which experienced a significant decrease in incidence, thereby narrowing the gap with other racial/ethnic groups. For IBD, an identical pattern of early-onset IBD among non-Hispanic Blacks (NHBs) compared to Hispanics was showed with coincidence test p = 0.1522, and a parallel pattern was observed among late-onset patients for both sexes (p = 0.5087). CONCLUSION Late-onset HCC continues to rise, except for NHB and AI/AN/API, where incidence rates have started to decrease over the past 4-5 years. Early and late-onset ICC incidence continues to increase across all racial/ethnic groups.
Collapse
Affiliation(s)
- Mei-Chin Hsieh
- Epidemiology and Population Health Program, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3Rd Floor, , New Orleans, LA, 70112, USA.
- Louisiana Tumor Registry, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
| | - Kendra L Ratnapradipa
- Epidemiology Department, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Laura Rozek
- Oncology Academic Department, Georgetown University Medical Center, Washington, DC, 20057, USA
- Cancer Prevention and Control Program for Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA
| | - Shengdi Wen
- Epidemiology and Population Health Program, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3Rd Floor, , New Orleans, LA, 70112, USA
| | - Yu-Wen Chiu
- Epidemiology and Population Health Program, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3Rd Floor, , New Orleans, LA, 70112, USA
| | - Edward S Peters
- Epidemiology Department, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| |
Collapse
|
32
|
Wang MF, Li TZ, Ma YB, Wang YC, Li QH, Li FJ, Chen JJ. Artemyriantholidimers A-G, undescribed guaiane-type sesquiterpenoid dimers from Artemisia myriantha and their antihepatoma activities. PHYTOCHEMISTRY 2025; 233:114409. [PMID: 39826810 DOI: 10.1016/j.phytochem.2025.114409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 01/22/2025]
Abstract
Artemyriantholidimers A-G (1-7), seven undescribed guaiane-type sesquiterpenoid dimers (GSDs), and 27 known compounds (8-34) were isolated from Artemisia myriantha (Asteraceae). Their structures and relative configurations were elucidated based on the comprehensive analyses of UV, IR, MS, NMR data, quantum chemical NMR calculations with DP4+ probability analyses, and the absolute configurations were elucidated by ECD calculations. The undescribed GSDs (1-7) were presumably formed via Diels-Alder reactions, and compounds 5-7 were rare GSDs with α-configuration of H-6'. Compounds 4-7 showed significant inhibition on HepG2, Huh7, and SK-Hep-1 cells with IC50 values ranging from 6.9 to 13.0 μM by antihepatoma assay. The best active compound 5 was deduced to be targeted on the protein AURKA of the p53 signaling pathway by network pharmacological analysis with a high bind affinity of AURKA (total score: -8.98) by molecular docking, and had a KD value of 62.4 μM by surface plasmon resonance assay.
Collapse
Affiliation(s)
- Meng-Fei Wang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China
| | - Tian-Ze Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - Yun-Bao Ma
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - Yong-Cui Wang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - Qi-Hao Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China
| | - Feng-Jiao Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China
| | - Ji-Jun Chen
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
| |
Collapse
|
33
|
Mao T, Xie Q, Zhao X, Jiang K, Yang M, Gao F. Indocyanine green fluorescence imaging (ICG-FI) in difficult laparoscopic hepatectomy for hepatocellular carcinoma: a retrospective propensity score-matched analysis. Surg Endosc 2025; 39:3400-3411. [PMID: 40216627 PMCID: PMC12041109 DOI: 10.1007/s00464-025-11707-3] [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: 02/07/2025] [Accepted: 03/30/2025] [Indexed: 05/01/2025]
Abstract
BACKGROUND Indocyanine green fluorescence imaging (ICG-FI) is increasingly used in laparoscopic hepatectomy (LH). However, its efficacy in enhancing both short- and long-term outcomes in difficult LH for hepatocellular carcinoma (HCC) compared with traditional white light (WL) LH remains unclear. METHODS This retrospective cohort study analyzed 573 patients who underwent LH between April 2018 and April 2023, stratified by the use of ICG-FI or WL. Propensity score matching (PSM, 1:1) was employed to minimize baseline discrepancies and reduce selection bias. Perioperative outcomes, overall survival (OS), and recurrence-free survival (RFS) were evaluated. Kaplan-Meier survival analysis was conducted to compare OS and RFS between groups, and Cox regression models were applied to identify independent prognostic factors. RESULTS Among the 573 patients who underwent LH, 178 were classified as high-difficulty hepatectomies, including 47 patients in the ICG-FI group and 131 in the WL group. After PSM, 78 patients were matched, with 39 patients in each group. In both unmatched and matched cohorts, the ICG-FI group demonstrated significantly lower conversion rates (2.6% vs. 15.4%, P = 0.048), shorter durations of drainage tube placement (7.0 [5.0, 8.0] vs. 7.0 [6.0, 9.5], P = 0.048), fewer severe postoperative complications (2.6% vs. 15.4%, P = 0.048), and reduced postoperative hospital stays (7 [4.5, 9] vs. 8 [7, 10], P = 0.045). Kaplan-Meier analysis revealed significantly improved RFS in the ICG-FI group compared with the WL group (P = 0.021). Independent predictors of RFS included ICG-FI, liver cirrhosis, and the presence of satellite nodules. Independent predictors of OS included LH performed at the expert difficulty level (HR = 2.875, 95% CI: 1.331-6.207, P = 0.007) and R0 resection (HR = 0.142, 95% CI: 0.028-0.734, P = 0.020). CONCLUSIONS ICG-FI demonstrates significant benefits in short-term outcomes and enhances RFS in patients undergoing difficult LH for HCC. However, its impact on OS warrants further validation through large-scale, multicenter prospective studies.
Collapse
Affiliation(s)
- Tianyang Mao
- Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Qingyun Xie
- Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Xin Zhao
- Department of Hepato-Pancreato-Biliary Surgery, People's Hospital of Leshan, Leshan, China
| | - Kangyi Jiang
- Department of Hepato-Pancreato-Biliary Surgery, People's Hospital of Leshan, Leshan, China
| | - Manyu Yang
- Department of Hepato-Pancreato-Biliary Surgery, People's Hospital of Leshan, Leshan, China
| | - Fengwei Gao
- Liver Transplantation Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.
| |
Collapse
|
34
|
Huang P, Rodriguez-Matos FJ, Qi J, Trehan R, Myojin Y, Zhu XB, Greten TF, Ma C. Hepatic immune environment differences among common mouse strains in models of MASH and liver cancer. JHEP Rep 2025; 7:101380. [PMID: 40342632 PMCID: PMC12060451 DOI: 10.1016/j.jhepr.2025.101380] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 05/11/2025] Open
Abstract
Background & Aims Inbred mouse strains are critical tools for studying immune regulation of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Here, we profiled mouse strain-associated hepatic immune differences, and performed mice-human cross-species immune comparisons. Methods Immune landscapes of C57BL/6, BALB/c, and FVB/N mice were compared under healthy, MASH, or HCC state using high-dimensional spectral flow cytometry (n = 4 per condition). MASH was induced by feeding methionine- and choline-deficient or Western diet + carbon tetrachloride. HCC was caused by hydrodynamic plasmid injection of MYC/sg-p53. Public mouse and human scRNA-seq datasets were used for validation and cross-species comparisons. Results In healthy mice, liver CD4+ T (24% vs. 14% vs. 34%, p <0.05) and B cells (36.5% vs. 35% vs.18%, p <0.05) varied the most among three strains. C57BL/6 mice showed TH1 dominance, whereas BALB/c and FVB/N mice had TH2 dominance (log[TH1:TH2] = 0.17, -0.31, -0.17). In MASH mice, expansion of liver myeloid cells and innate lymphocytes were commonly found, but changes of B cells (log(fold-change) = -0.38, -0.28, -0.58, p <0.05) and T subsets (e.g. CD4+ T log(fold-change) = -0.21, -0.07, -0.15, p <0.05) varied greatly among strains. MYC/sg-p53 HCC induced a consistent expansion of liver Tregs and CD8+ T cells (p <0.05), but differential shifts of liver immune landscape were seen among strains. The flow cytometry data was supported by public scRNA-seq datasets matching C57BL/6 background. Further cross-species comparison in MASH condition confirmed shared changes of adaptive lymphocytes between mice and humans. In two MASH models, BALB/c or C57BL/6 mice were more consistent to recapture loss of CD4+ T or B cells, respectively (p <0.05). Conclusions Substantial liver immune differences exist among common mouse strains. Mice can recapitulate certain human liver immune changes with strain variations. Impact and implications Our immune cell profiling study revealed that the liver immune environment can be quite different among common mouse strains both under healthy and pathologic states, such as steatohepatitis or neoplastic processes. Our results serve as a data resource for studies investigating liver immunology and provide valuable insights for the design of studies on various immune cells in the livers of mice.
Collapse
Affiliation(s)
- Patrick Huang
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Francisco J. Rodriguez-Matos
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jonathan Qi
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Rajiv Trehan
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yuta Myojin
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Xiao Bin Zhu
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tim F. Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, USA
| | - Chi Ma
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
35
|
Schulze K, Rose TD, Adlung L, Peschka M, Pagani F, Gorgulho J, Fründt TW, Labgaa I, Haber PK, Zimpel C, Castven D, Weinmann A, Garzia-Lezana T, Waldmann M, Renné T, Voß H, Moritz M, Orlikowski D, Schlüter H, Baumbach J, Schwartz M, Lohse AW, Huber S, Sangro B, Macias RI, Izquierdo-Sanchez L, Banales JM, Wege H, Marquardt JU, Villanueva A, Pauling JK, von Felden J. Metabolomic liquid biopsy dynamics predict early-stage HCC and actionable candidates of human hepatocarcinogenesis. JHEP Rep 2025; 7:101340. [PMID: 40290517 PMCID: PMC12023797 DOI: 10.1016/j.jhepr.2025.101340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 01/16/2025] [Accepted: 01/22/2025] [Indexed: 04/30/2025] Open
Abstract
Background & Aims Actionable candidates of hepatocarcinogenesis remain elusive, and tools for early detection are suboptimal. Our aim was to demonstrate that serum metabolome profiles reflect the initiation of hepatocellular carcinoma (HCC) and enable the identification of biomarkers for early HCC detection and actionable candidates for chemoprevention. Methods This global cohort study included 654 patients and 801 biospecimens. Following serum metabolome profiling across the spectrum of hepatocarcinogenesis, we conducted a phase II biomarker case-control study for early HCC detection. Findings were independently validated through in silico analysis, mRNA sequencing, and proteome profiling of primary HCC and non-tumoral tissue, and in vitro experiments. Results Aspartic acid, glutamic acid, taurine, and hypoxanthine were differentially abundant in the serum across chronic liver disease, cirrhosis, initial HCC, and progressed HCC, independent of sex, age, and etiology. In a phase II biomarker case-control study, a blood-based metabolite signature yielded an AUC of 94% to discriminate between patients with early-stage HCC and controls with cirrhosis, including independent validation. Unsupervised biclustering (MoSBi), lipid network analysis (LINEX2), and pathway enrichment analysis confirmed alterations in amino acid-, lipid-, and nucleotide-related pathways. In tumor tissue, these pathways were significantly deregulated regarding gene and protein expression in two independent datasets, including actionable targets RRM2, GMPS, BCAT1, PYCR2, and NEU1. In vitro knockdown confirmed a functional role in proliferation and migration, as exemplified for PYCR2. Conclusions These findings demonstrate that serum metabolome profiling indicates deregulated metabolites and pathways during hepatocarcinogenesis. Our liquid biopsy approach accurately detects early-stage HCC outperforming currently recommended surveillance tools and facilitates identification of actionable candidates for chemoprevention. Impact and implications Deregulated cellular metabolism is a hallmark of cancer. In smaller studies, circulating metabolite profiles have been associated with HCC, although mainly in the context of fatty liver disease. Translation strategies for primary prevention or early detection are lacking. In this global study, we present an unsupervised landscape of the altered serum metabolome profile during hepatocarcinogenesis, independent of age, sex, and etiology. We provide a blood-based metabolite signature that accurately identifies early-stage HCC in a phase II biomarker study including independent validation. Further RRM2, GMPS, BCAT1, PYCR2, and NEU1 are identified in tumor tissue as actionable candidates for prevention. Our data provide the rationale for clinical trials testing liquid biopsy metabolome-based signatures for early HCC detection and the development of chemoprevention strategies.
Collapse
Affiliation(s)
- Kornelius Schulze
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- ERN-RARE-LIVER, Hamburg, Germany
| | - Tim Daniel Rose
- LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Munich, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Lorenz Adlung
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), and Center for Biomedical AI (bAIome), Hamburg, Germany
- Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Manuela Peschka
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Newborn Screening and Metabolic Laboratory, Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Francesca Pagani
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Joao Gorgulho
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- University Cancer Center Hamburg–Hubertus Wald Tumorzentrum, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Thorben W. Fründt
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- ERN-RARE-LIVER, Hamburg, Germany
| | - Ismail Labgaa
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Philipp K. Haber
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Carolin Zimpel
- Department of Medicine I, University Medical Center Schleswig-Holstein-Campus Lübeck, Germany
| | - Darko Castven
- Department of Medicine I, University Medical Center Schleswig-Holstein-Campus Lübeck, Germany
| | - Arndt Weinmann
- I. Department of Medicine, University Medical Center Mainz, Germany
| | - Teresa Garzia-Lezana
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Moritz Waldmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Renné
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Hannah Voß
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Manuela Moritz
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dorian Orlikowski
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hartmut Schlüter
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan Baumbach
- Chair of Computational Systems Biology, University of Hamburg, 22607 Hamburg, Germany
| | - Myron Schwartz
- Recanati Miller Transplant Institute, The Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA
| | - Ansgar W. Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- ERN-RARE-LIVER, Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- ERN-RARE-LIVER, Hamburg, Germany
| | - Bruno Sangro
- Liver Unit, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
| | - Rocio I.R. Macias
- Center for the Study of Liver and Gastrointestinal Diseases (CIBEREHD), Carlos III National Institute of Health, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Laura Izquierdo-Sanchez
- Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute–Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBEREHD, Donostia-San Sebastian, Spain
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute–Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBEREHD, Donostia-San Sebastian, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Henning Wege
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- ERN-RARE-LIVER, Hamburg, Germany
| | - Jens U. Marquardt
- Department of Medicine I, University Medical Center Schleswig-Holstein-Campus Lübeck, Germany
- I. Department of Medicine, University Medical Center Mainz, Germany
| | - Augusto Villanueva
- Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Josch Konstantin Pauling
- LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Munich, Germany
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
| | - Johann von Felden
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- ERN-RARE-LIVER, Hamburg, Germany
| |
Collapse
|
36
|
Tan EY, Danpanichkul P, Yong JN, Yu Z, Tan DJH, Lim WH, Koh B, Lim RYZ, Tham EKJ, Mitra K, Morishita A, Hsu YC, Yang JD, Takahashi H, Zheng MH, Nakajima A, Ng CH, Wijarnpreecha K, Muthiah MD, Singal AG, Huang DQ. Liver cancer in 2021: Global Burden of Disease study. J Hepatol 2025; 82:851-860. [PMID: 39481652 DOI: 10.1016/j.jhep.2024.10.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/12/2024] [Accepted: 10/20/2024] [Indexed: 11/02/2024]
Abstract
BACKGROUND & AIMS The epidemiology of adult primary liver cancer continues to evolve, owing to the increasing prevalence of metabolic disease, rising alcohol consumption, advances in vaccination for HBV, and antiviral therapy for HCV. Disparities in care and the burden of liver cancer between populations persist. We assess trends in the burden of liver cancer and contributions by various etiologies across 204 countries and territories from 2010 to 2021. METHODS Utilizing the methodological framework of the Global Burden of Disease Study 2021, we analyzed global and regional temporal trends in incidence and mortality, and the contributions of various etiologies of liver disease. RESULTS In 2021, there were an estimated 529,202 incident cases and 483,875 deaths related to liver cancer. From 2010 to 2021, global liver cancer incident cases and deaths increased by 26% and 25%, respectively. Age-standardized incidence rates (ASIRs) and death rates (ASDRs) for liver cancer declined globally, but rose in the Americas and Southeast Asia. HBV remained the dominant cause of global incident liver cancer cases and deaths. MASLD (metabolic dysfunction-associated steatotic liver disease) was the only etiology of liver cancer with rising ASIRs and ASDRs. By contrast, ASIRs and ASDRs remained stable for alcohol-related liver cancer, and declined for HBV- and HCV-related liver cancer. CONCLUSIONS While age-adjusted incidence and deaths from liver cancer have started to decline, the absolute number of incident cases and deaths continues to increase. Population growth and aging contribute to the observed disconnect in the temporal trends of absolute cases and rates. Disparities remain, and the incidence and mortality associated with MASLD-related liver cancer continue to rise. IMPACT AND IMPLICATIONS Liver cancer remains a major cause of death globally, but its causes and burden in various regions are changing. This study highlights that new diagnoses and deaths related to liver cancer continue to rise. Age-adjusted death rates of liver cancer related to viral hepatitis are declining but remain high. By contrast, age-adjusted death rates of liver cancer related to MASLD (metabolic dysfunction-associated steatotic liver disease) are rising. Sustained efforts and resources are needed to eliminate viral hepatitis, reverse current trends in heavy alcohol use, and tackle the metabolic risk factors of MASLD.
Collapse
Affiliation(s)
- En Ying Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Pojsakorn Danpanichkul
- Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas, USA
| | - Jie Ning Yong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Zhenning Yu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Benjamin Koh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ryan Yan Zhe Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ethan Kai Jun Tham
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kartik Mitra
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Yao-Chun Hsu
- Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Hirokazu Takahashi
- Liver Center, Faculty of Medicine, Saga University Hospital, Saga University, Saga, Japan
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Cheng Han Ng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore; Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine, Phoenix, Arizona, USA
| | - Mark D Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Amit G Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Daniel Q Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| |
Collapse
|
37
|
Altaf A, Khalil M, Akabane M, Rashid Z, Kawashima J, Zindani S, Ruzzenente A, Ratti F, Marques H, Cauchy F, Lam V, Poultsides G, Aucejo F, Kitago M, Popescu I, Martel G, Gleisner A, Bauer TW, Hugh T, Bhimani N, Shen F, Endo I, Pawlik TM. Up-front resection for hepatocellular carcinoma: Assessing futility in the preoperative setting. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109594. [PMID: 39826445 DOI: 10.1016/j.ejso.2025.109594] [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: 12/03/2024] [Revised: 12/28/2024] [Accepted: 01/09/2025] [Indexed: 01/22/2025]
Abstract
OBJECTIVE We sought to develop a predictive model to preoperatively identify patients with hepatocellular carcinoma (HCC) at risk of undergoing futile upfront liver resection (LR). METHODS Patients undergoing curative-intent LR for HCC were identified from a large multi-institutional database. Futile LR was defined by death or disease recurrence within six months postoperatively. Backward logistic regression was performed to identify factors associated with futility. Additionally, binary criteria were established for surgical candidacy, aiming to keep the likelihood of futility below 20 %. RESULTS Among 1633 patients with HCC, 264 (16.2 %) underwent futile upfront LR. Tumor burden score (TBS) (coefficient: 0.083, 95%CI: 0.067-0.099), alpha-fetoprotein (AFP) (coefficient: 0.254, 95%CI: 0.195-0.310), and albumin-bilirubin (ALBI) grade 2/3 (coefficient: 0.566, 95%CI: 0.420-0.718) were independently associated with an increased risk of futile LR. The model demonstrated strong discrimination and calibration in both derivation and validation cohorts. Low, intermediate, and high-risk groups were determined based on the risk model, each with an escalating likelihood of futility, worse histological features, and worse survival outcomes. Six distinct conditions based on AFP-adjusted-to-TBS criteria were established, all with a futility likelihood of less than 20 %. Patients fulfilling these criteria had significantly better long-term recurrence-free and overall survival. The futility risk model was made available online for wide clinical applicability: (https://altaf-pawlik-hcc-futilityofsurgery-calculator.streamlit.app/). CONCLUSION A preoperative risk model and AFP-adjusted-to-TBS criteria were developed and validated to predict the likelihood of futile LR among patients with HCC. This pragmatic clinical tool may assist clinicians in preoperative decision-making, helping them avoid futile surgery unlikely to offer long-term benefits.
Collapse
Affiliation(s)
- Abdullah Altaf
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | - Mujtaba Khalil
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | - Miho Akabane
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | - Zayed Rashid
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | - Jun Kawashima
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | - Shahzaib Zindani
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States
| | | | | | - Hugo Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | - François Cauchy
- Department of Hepatobiliopancreatic Surgery, APHP, Beaujon Hospital, Clichy, France
| | - Vincent Lam
- Department of Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - George Poultsides
- Department of Surgery, Stanford University, Stanford, CA, United States
| | - Federico Aucejo
- Department of Surgery, Cleveland Clinic., Cleveland, OH, United States
| | - Minoru Kitago
- Department of Surgery, Keio University, Tokyo, Japan
| | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | | | - Ana Gleisner
- Department of Surgery, University of Colorado, Aurora, CO, United States
| | - Todd W Bauer
- Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Tom Hugh
- Department of Surgery, School of Medicine, The University of Sydney, Sydney, NSW, Australia
| | - Nazim Bhimani
- Department of Surgery, School of Medicine, The University of Sydney, Sydney, NSW, Australia
| | - Feng Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Itaru Endo
- Department of Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, United States.
| |
Collapse
|
38
|
Gu Y, Guo C, Liu Z, Zhang Y, Han X, Zhang X, Zhao S, Wang H, Zhang T. The trend in incidence of non-alcoholic fatty liver disease and its impact on cirrhosis and liver cancer: An analysis from Global Burden of Disease 2021. Public Health 2025; 242:79-86. [PMID: 40037155 DOI: 10.1016/j.puhe.2025.02.028] [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: 08/21/2024] [Revised: 02/04/2025] [Accepted: 02/20/2025] [Indexed: 03/06/2025]
Abstract
OBJECTIVES We aimed to recognize the burden of NAFLD and support public health policy development for its prevention and management. STUDY DESIGN A cross-sectional analysis of GBD 2021 results was conducted. METHODS We collected incidence data on NAFLD from 1990 to 2021 using Global Burden of Disease Study in 2021. Estimated annual percentage changes (EAPCs) in NAFLD age standardized incidence rate (ASR) were calculated to quantify the temporal trends in NAFLD ASR. Bayesian age-period-cohort models were constructed to project NAFLD incidence rates and cases up to 2050. Additionally, we assessed the percentage of cirrhosis and liver cancer attributable to NAFLD. RESULTS Globally, the newly-occurred cases of NAFLD increased by 94.49 % from 24, 856, 159 in 1990 to 48, 353, 272 in 2021. The case number will further increase to 78,602,984 in 2050, and ASR will increase from 5.93 per 1000 in 2021 to 7.26 per 1000 in 2050. The most pronounced increases were observed in young people and men. In 2021, NAFLD accounted for 82.7 % of cirrhosis and other chronic liver diseases and 8.0 % of liver cancer cases. CONCLUSIONS From 1990 to 2021, the incidence of NAFLD has been continuously increasing and is expected to continue rising until 2050. The increases in young people and men highlight their priority in future schedules. The rising proportions of cirrhosis and liver cancer caused by NAFLD further underscore the serious health risks.
Collapse
Affiliation(s)
- Yu Gu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
| | - Chengnan Guo
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China; Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai, 200032, China
| | - Zhenqiu Liu
- Fudan University Taizhou Institute of Health Sciences, Taizhou, 225300, China; State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, 200032, China
| | - Yujiao Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China; Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai, 200032, China
| | - Xinyu Han
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
| | - Xin Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
| | - Shuzhen Zhao
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
| | - Haili Wang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China
| | - Tiejun Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China; Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai, 200032, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, 225300, China; Yiwu Research Institute, Fudan University, Yiwu, 200032, China.
| |
Collapse
|
39
|
Lai G, Xie B, Zhang C, Zhong X, Deng J, Li K, Liu H, Zhang Y, Liu A, Liu Y, Fan J, Zhou T, Wang W, Huang A. Comprehensive analysis of immune subtype characterization on identification of potential cells and drugs to predict response to immune checkpoint inhibitors for hepatocellular carcinoma. Genes Dis 2025; 12:101471. [PMID: 40092490 PMCID: PMC11907441 DOI: 10.1016/j.gendis.2024.101471] [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: 10/17/2023] [Revised: 04/12/2024] [Accepted: 11/02/2024] [Indexed: 03/19/2025] Open
Abstract
Immunosubtyping enables the segregation of immune responders from non-responders. However, numerous studies failed to focus on the integration of cellular heterogeneity and immunophenotyping in the prediction of hepatocellular carcinoma (HCC) patients' response to immune checkpoint inhibitors (ICIs). We categorized HCC patients into various immune subtypes based on feature scores linked to ICI response. Single-cell sequencing technology was to investigate the cellular heterogeneity of different immune subtypes and acquire significant ICI response-associated cells. Candidate drugs were identified using a blend of various drug databases and network approaches. HCC patients were divided into two distinct immune subtypes based on characterization scores of 151 immune-related gene sets. Patients in both subtypes showed varying overall survival, immunity levels, biological activities, and TP53 mutation rates. Subtype 1-related natural killer cells showed a positive correlation with immune-promoting scores but a negative correlation with immune-suppressing scores. Notably, docetaxel sensitivity in HCC patients rose as the levels of subtype 1-related natural killer cells increased. Our study demonstrated that immune subtypes have cellular heterogeneity in predicting response to ICIs. A combination of subtype 1-associated natural killer cells and docetaxel may offer new hope for ICI treatment in HCC.
Collapse
Affiliation(s)
- Guichuan Lai
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Biao Xie
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Cong Zhang
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Xiaoni Zhong
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Jielian Deng
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Kangjie Li
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Hui Liu
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Yuan Zhang
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Anbin Liu
- Department of Applied Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Yi Liu
- Department of Applied Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Jie Fan
- Department of Epidemiology, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Tianyi Zhou
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Wei Wang
- Department of Applied Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| |
Collapse
|
40
|
Li Y, Zhong JH, Zhu XD, Han CY, Wang JB, Liu HZ, Hu K, Pan YX, Sun HC, Peng T, Liu LX, Zeng YY, Zhou LD, Xu L, Wang NY. Efficacy and safety of combined targeted therapy and immunotherapy versus targeted monotherapy in older patients with uHCC. Front Oncol 2025; 15:1515640. [PMID: 40356761 PMCID: PMC12066334 DOI: 10.3389/fonc.2025.1515640] [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: 10/23/2024] [Accepted: 03/31/2025] [Indexed: 05/15/2025] Open
Abstract
Background The prevalence of hepatocellular carcinoma (HCC) among older patients is rising due to the aging population. This study aimed to compare the efficacy and safety of targeted therapy alone versus its combination with immunotherapy in older patients (≥ 65 years old) with unresectable HCC (uHCC). Methods We retrospectively analyzed 158 patients aged ≥ 65 diagnosed with uHCC who received targeted therapy alone or in combination with immunotherapy from the CLEAP database between March 2019 and July 2023. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety assessments for adverse events (AEs). Results The ORR was 3.6% in the targeted monotherapy group compared to 29.4% in the combination therapy group, while the DCRs were 53.6% and 54.9%, respectively. Survival analysis indicated a median PFS of 7.3 months for monotherapy versus 13.2 months for combination therapy (P = 0.137) and a median OS of 16.0 months versus 20.0 months, respectively (P = 0.140). AEs occurred in 44.6% of the monotherapy group and 58.8% in the combination therapy group, with 20.5% in the combination group withdrawing due to adverse reactions, significantly higher than in monotherapy group. Conclusion Among older patients with uHCC, the combination therapy demonstrated higher ORR and longer PFS and OS, although it had higher incidences of AEs and drug withdrawal.
Collapse
Affiliation(s)
- Yu Li
- Department of Phase I Clinical Trial Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, The Affiliated Cancer Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiao-Dong Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chuang-Ye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jia-Bei Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei, Anhui, China
| | - Hong-Zhi Liu
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Kuan Hu
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yang-Xun Pan
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Lian-Xin Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei, Anhui, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Le-Du Zhou
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Li Xu
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Nan-Ya Wang
- Department of Phase I Clinical Trial Center, The First Hospital of Jilin University, Changchun, Jilin, China
| |
Collapse
|
41
|
Liu ZH, Shi JJ, Zhang M, Dang SS. Advances in application of serum biomarkers for screening and early diagnosis of hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2025; 33:251-260. [DOI: 10.11569/wcjd.v33.i4.251] [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: 03/17/2025] [Revised: 04/12/2025] [Accepted: 04/17/2025] [Indexed: 04/28/2025] Open
Abstract
Hepatocellular carcinoma (HCC) represents a major global health challenge, with early detection through surveillance of high-risk populations remaining critical for improving clinical outcomes. Serum biomarkers play a crucial role in the early detection of HCC. Currently, commonly used serological markers for HCC include alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, and the Lens culinaris agglutinin-reactive fraction of AFP. Other potential biomarkers under investigation include glypican-3, osteopontin, alpha-L-fucosidase, Dickkopf-1, heat shock protein 90α, and Golgi protein 73. With the advancement of liquid biopsy technologies, novel markers such as circulating tumor DNA, circulating tumor cells, microRNAs, and long non-coding RNAs have emerged as promising tools for early screening and diagnosis of HCC. This review aims to summarize the research progress and clinical applications of these biomarkers related to liver cancer, providing scientific evidence to enhance early diagnosis rates, improve prognosis, and ultimately reduce HCC-related mortality.
Collapse
Affiliation(s)
- Zi-Han Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 71004, Shaanxi Province, China
| | - Juan-Juan Shi
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 71004, Shaanxi Province, China
| | - Meng Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 71004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 71004, Shaanxi Province, China
| |
Collapse
|
42
|
Altaf A, Kiran A, Sarwar M, Maqbool T, Sharif S, Iqbal H, Farooq S, Ali Q, Han S, Ahmad A. Therapeutic potential of Bacopa monnieri extracts against hepatocellular carcinoma through in-vitro and computational studies. PLoS One 2025; 20:e0321445. [PMID: 40294146 PMCID: PMC12036942 DOI: 10.1371/journal.pone.0321445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 03/06/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Among various cancers, primary liver cancer is the seventh most diagnosed malignancy and is the second most prevalent contributor to cancer-causing deaths. During conventional treatment, the recurrence of disease, low drug inefficacy, and severe side effects are the main limitations. Recently, natural anticancer medicines from the Middle East, Korea, China, Europe, North America, and India have attracted a lot of interest due to their low side effects and better remedial properties. The current study investigated the antioxidative and anticancer effects of ethanolic (BME) and n-hexane (BMH) extracts of B. monnieri (L.) Wettst. METHODS In the current study, phytochemical profiling was done using gas chromatography-mass spectrometry (GC-MS) analysis. The antioxidant potential was measured using DPPH, nitric oxide, superoxide anion, and hydrogen peroxide assays, while the cell viability and apoptotic effect were measured by MTT, crystal violet, and annexin V/PI protocols, respectively. RESULTS Higher concentrations of total phenolic contents (274.92±3.52 mgGAE/g), total flavonoid contents (141.99±4.14 mgQE/g) and tannins (55.49±4.63 mgTAE/g) were observed in BME extract with strong antioxidant potential than BMH extract. Also, BME extract showed higher cytotoxicity with less IC50 value (24.70 μg/mL) and a lower percentage of cell viability, while the same extract exhibited 58.65% apoptosis against HepG2 cells in comparison to cisplatin and BMH extract. Furthermore, Spiro[(tricyclo[6.2.2.0(2,7)]dodeca-5,9-diene)-4,1'-cyclobutane]-11,2'-dione from BME extract showed the lead docking score of -8.8, -8.1 and -7.8 kcal/mol against TGF-βR1, TNF-α, and iNOS, respectively. CONCLUSION In conclusion, the ethanolic extract of B. monnieri has a significant potential for becoming a potent anticancer drug that effectively treats liver damage, including HCC.
Collapse
Affiliation(s)
- Awais Altaf
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
- Faculty of Health Sciences, Equator University of Science and Technology, Masaka, Uganda,
| | - Asia Kiran
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Muhammad Sarwar
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Tahir Maqbool
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Sumaira Sharif
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Hana’a Iqbal
- National Institute of Virology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Saba Farooq
- National Institute of Virology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Qurban Ali
- Department of Plant Breeding and Genetics, University of the Punjab, Lahore, Pakistan
| | - Shiming Han
- School of Biological Sciences and Technology, Liupanshui Normal University, Liupanshui, China
| | - Ajaz Ahmad
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
43
|
Liu ZH, Shi JJ, Zhang M, Dang SS. Advances in application of serum biomarkers for screening and early diagnosis of hepatocellular carcinoma. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2025; 33:251-260. [DOI: https:/dx.doi.org/10.11569/wcjd.v33.i4.251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
|
44
|
Xu Y, Yu J. TMC5 as a Marker of Tumor-Associated Telocytes in Hepatocellular Carcinoma. FRONT BIOSCI-LANDMRK 2025; 30:36583. [PMID: 40302342 DOI: 10.31083/fbl36583] [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: 12/25/2024] [Revised: 03/07/2025] [Accepted: 03/19/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND Tumor-associated telocytes (TATCs) perform a pivotal role in hepatocellular carcinoma (HCC) progression and correlate with poor patient outcomes. This study aims to identify specific markers of TATCs in HCC using single-nucleus RNA sequencing (snRNA-seq) and transcriptomic analyses. METHODS Comprehensive snRNA-seq and transcriptomic profiling were performed on HCC and adjacent non-cancerous tissues to detect differential expressed genes (DEGs) in TATCs. Bioinformatics tools, including STING and Cytoscape software, were employed to analyze protein-protein interactions and hub genes. Immune cell interactions were assessed via ligand-receptor network analysis. RESULT TATCs constituted 0.35% of cells in HCC tissues, with reduced proportions compared to para-cancerous tissues (0.35% vs 8.19%). Hub genes, including TOP2A (DNA topoisomerase Ⅱ alpha), BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B), KIF11 (kinesin family member 11), and CENPF (centromere protein F) were identified in telocytes (TCs). Transcriptomics revealed 622 upregulated and 758 downregulated genes in TATCs versus TCs. TMC5 (transmembrane channel like 5) and SLC35F3 (solute carrier family 35 member F3) emerged as unique TATCs biomarkers, revealing significant associations with poor overall survival (OS) in HCC patients (HR = 1.499 for TMC5; HR = 1.562 for SLC35F3). CONCLUSION TMC5 and SLC35F3 are promising biomarkers for TATCs in HCC, warranting further validation to explore their clinical and therapeutic implications.
Collapse
Affiliation(s)
- Ying Xu
- Department of General Surgery, Shandong Provincial Third Hospital, Shandong University, 250031 Jinan, Shandong, China
| | - Jing Yu
- Department of Pathology, Shandong Provincial Third Hospital, Shandong University, 250031 Jinan, Shandong, China
| |
Collapse
|
45
|
Wang ZB, Zhu B, Meng MM, Wu YF, Zhang Y, Li DZ, Tian H, Wang FC, Lv YF, Ye QX, Liu FQ. Nomogram for predicting survival after transjugular intrahepatic portosystemic shunt in portal hypertension patients with bleeding. World J Gastrointest Surg 2025; 17:104884. [PMID: 40291885 PMCID: PMC12019031 DOI: 10.4240/wjgs.v17.i4.104884] [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: 01/05/2025] [Revised: 02/17/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Portal hypertension (PHT) is a life-threatening complication of cirrhosis, often resulting in gastrointestinal bleeding that requires transjugular intrahepatic portosystemic shunt (TIPS). While TIPS effectively reduces portal pressure, predicting long-term survival remains challenging due to the multifactorial nature of patient outcomes. Accurate survival prediction tools are lacking, and existing models often omit critical factors such as portal vein diameter. This study aimed to develop and validate a nomogram incorporating key clinical and biochemical variables to predict 1-year and 2-year survival following TIPS in PHT patients. We hypothesized that this model would provide improved risk stratification and guide clinical decisions. AIM To develop and validate a nomogram for predicting 1-year and 2-year survival in PHT patients post-TIPS. METHODS This retrospective cohort study included 848 TIPS-treated PHT patients with gastrointestinal bleeding from two tertiary hospitals (2013-2021). Mortality was the primary endpoint. Predictive variables were selected using least absolute shrinkage and selection operator regression, and a nomogram was developed with Cox regression to predict 1-year and 2-year survival. Model performance was evaluated through receiver operating characteristic curves, calibration plots, and decision curve analysis. RESULTS The mean age of the included (848) patients was 53.00 years ± 12.51, where 69.58% were men. Results showed that portal vein diameter, serum creatinine, potassium, and alpha-fetoprotein were the independent predictors of post-TIPS survival. Besides, the model showed strong discriminatory ability (C-index, 0.816 in the training set; 0.827 in the validation set) and good calibration. The area under the curve for 1-year and 2-year survival in the training set were 0.890 [95% confidence interval (CI): 0.802-0.948] and 0.838 (95%CI: 0.803-0.869), respectively. The area under the curve for 1-year and 2-year survival in the validation set were 0.934 (95%CI: 0.815-0.987) and 0.864 (95%CI: 0.811-0.907), respectively. CONCLUSION The developed nomogram could reliably predict 1-year and 2-year survival in patients undergoing TIPS for PHT-induced gastrointestinal bleeding.
Collapse
Affiliation(s)
- Zhi-Bin Wang
- Center for Minimally Invasive Treatment of Liver Diseases, Beijing Shijitan Hospital, Capital Medical University, Beijing 100080, China
| | - Bing Zhu
- Center for Diagnosis and Treatment of Hepatic Vascular Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
| | - Ming-Ming Meng
- Center for Minimally Invasive Treatment of Liver Diseases, Beijing Shijitan Hospital, Capital Medical University, Beijing 100080, China
| | - Yi-Fan Wu
- Center for Minimally Invasive Treatment of Liver Diseases, Beijing Shijitan Hospital, Capital Medical University, Beijing 100080, China
| | - Yu Zhang
- Center for Minimally Invasive Treatment of Liver Diseases, Beijing Shijitan Hospital, Capital Medical University, Beijing 100080, China
| | - Dong-Ze Li
- Center for Diagnosis and Treatment of Hepatic Vascular Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
| | - Hua Tian
- Center for Diagnosis and Treatment of Hepatic Vascular Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
| | - Fu-Chuan Wang
- Center for Diagnosis and Treatment of Hepatic Vascular Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
| | - Yi-Fan Lv
- Center for Minimally Invasive Treatment of Liver Diseases, Beijing Shijitan Hospital, Capital Medical University, Beijing 100080, China
| | - Qiu-Xia Ye
- Center for Minimally Invasive Treatment of Liver Diseases, Beijing Shijitan Hospital, Capital Medical University, Beijing 100080, China
| | - Fu-Quan Liu
- Center for Minimally Invasive Treatment of Liver Diseases, Beijing Shijitan Hospital, Capital Medical University, Beijing 100080, China
- Center for Diagnosis and Treatment of Hepatic Vascular Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
| |
Collapse
|
46
|
Luo S, Huang Z, Dai Y, Wang S, Yu W, Li Z, Pu Q, Yang L, Yang T, Tang Y, Wang Z, Wang J, Wang J. Xihuang pill suppressed primary liver cancer growth by downregulation of AFP and YAP signaling. JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119891. [PMID: 40294663 DOI: 10.1016/j.jep.2025.119891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 04/13/2025] [Accepted: 04/26/2025] [Indexed: 04/30/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Xihuang Pill (XHP) is a traditional Chinese medicine formula that was originally used to treat malignant ulcers. Recent studies revealed its therapeutic effects on various malignant tumors. However, its potential efficacy and mechanisms in primary liver cancer (PLC) were not thoroughly investigated. AIM OF THE STUDY This study aimed to elucidate the efficacy and potential mechanisms of XHP in the treatment of PLC. METHODS An orthotopic PLC mice model was established adopting hydrodynamic tail vein injection method. Human liver cancer cell lines and organoids were utilized to assess the effect of XHP in vitro. The expressions of alpha-fetoprotein (AFP) and Yes-associated protein (YAP) were evaluated with western blotting. The mRNA expressions of YAP downstream targets were detected with qRT-PCR. Data from Liver Hepatocellular Carcinoma Collection of the Cancer Genome Atlas (TCGA-LIHC) were extracted to identify the potential targets of HCC. The major active components of XHP methanol extract and XHP medicated serum were detected by UHPLC-MS/MS. Human liver cancer cell lines were used to assess the efficacy and potential mechanisms of these active components in XHP in vitro. Finally, molecular docking was conducted to predict the binding affinities of XHP's active components with AFP and YAP. RESULTS XHP inhibited PLC tumor growth in the mice model with decreased AFP and Ki-67 index. In vitro, XHP suppressed the proliferation and migration of liver cancer cell lines in a time- and dose-dependent manner. Furthermore, even with a low concentration (5 mg/mL), XHP paralyzed the growth of PLC organoids derived from patients. Mechanistically, XHP downregulated the expression of AFP and YAP signaling in vitro and in vivo. UHPLC-MS/MS analysis identified 25 active components in XHP medicated serum. Among them, certain active compounds suppressed PLC cell proliferation and downregulated AFP and YAP signaling, suggesting their therapeutic potentials in PLC. Molecular docking indicated that several components in XHP exhibited strong binding affinities with both AFP and YAP. CONCLUSION XHP inhibited PLC growth by suppressing AFP and YAP signaling. This study provides an experimental basis for XHP application in PLC treatment.
Collapse
Affiliation(s)
- Sha Luo
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yuewen Dai
- Beijing Fengtai Hospital of Integrated Traditional Chinese and Western Medicine, Beijing, China.
| | - Shuyang Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
| | - Wantao Yu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
| | - Zhihan Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
| | - Qing Pu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
| | - Lihui Yang
- Oncology Department, The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an, China.
| | - Tianyi Yang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
| | - Yu Tang
- Center of Pharmaceutical Technology, Tsinghua University, Beijing, China.
| | - Zhang Wang
- College of Ethnomedicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Jiabo Wang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; School of Traditional Chinese Medicine, Capital Medical University, Beijing, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing, China.
| | - Jingxiao Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China; Capital Medical University Research and Translational Laboratory for Traditional Chinese Medicine in the Prevention and Treatment of Infectious Severe Hepatitis, Beijing, China.
| |
Collapse
|
47
|
He J, Li S, Xiong Y, Yao Y, Wang S, Wang S, Wang S. Hepatocellular carcinoma 18F-FDG PET/CT kinetic parameter estimation based on the advantage actor-critic algorithm. Med Phys 2025. [PMID: 40268713 DOI: 10.1002/mp.17851] [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: 04/21/2024] [Revised: 04/04/2025] [Accepted: 04/06/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Kinetic parameters estimated with dynamic 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) help characterize hepatocellular carcinoma (HCC), and deep reinforcement learning (DRL) can improve kinetic parameter estimation. PURPOSE The advantage actor-critic (A2C) algorithm is a DRL algorithm with neural networks that seek the optimal parameters. The aim of this study was to preliminarily assess the role of the A2C algorithm in estimating the kinetic parameters of 18F-FDG PET/CT in patients with HCC. MATERIALS AND METHODS 18F-FDG PET data from 14 liver tissues and 17 HCC tumors obtained via a previously developed, abbreviated acquisition protocol (5-min dynamic PET/CT imaging supplemented with 1-min static imaging at 60 min) were prospectively collected. The A2C algorithm was used to estimate kinetic parameters with a reversible double-input, three-compartment model, and the results were compared with those of the conventional nonlinear least squares (NLLS) algorithm. Fitting errors were compared via the root-mean-square errors (RMSEs) of the time activity curves (TACs). RESULTS Significant differences in K1, k2, k3, k4, fa, and vb according to the A2C algorithm and k3, fa, and vb according to the NLLS algorithm were detected between HCC and normal liver tissues (all p < 0.05). Furthermore, A2C demonstrated superior diagnostic performance over NLLS in terms of k3 and vb (both p < 0.05 in the Delong test). Notably, A2C yielded a smaller fitting error for normal liver tissue (0.62 ± 0.24 vs. 1.04 ± 1.00) and HCC tissue (1.40 ± 0.42 vs. 1.51 ± 0.97) than did NLLS. CONCLUSIONS Compared with the conventional postreconstruction NLLS method, the A2C algorithm can more precisely estimate 18F-FDG kinetic parameters with a reversible double-input, three-compartment model for HCC tumors, attaining better TAC fitting with a lower RMSE.
Collapse
Affiliation(s)
- Jianfeng He
- Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Yunnan Key Laboratory of Artificial Intelligence, Kunming, Yunnan, China
| | - Siming Li
- Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Yunnan Key Laboratory of Artificial Intelligence, Kunming, Yunnan, China
| | - Yiwei Xiong
- Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Yunnan Key Laboratory of Artificial Intelligence, Kunming, Yunnan, China
| | - Yu Yao
- Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Yunnan Key Laboratory of Artificial Intelligence, Kunming, Yunnan, China
| | - Siyu Wang
- PET/CT Center, Affiliated Hospital of Kunming University of Science and Technology, First People's Hospital of Yunnan, Kunming, China
| | - Sidan Wang
- PET/CT Center, Affiliated Hospital of Kunming University of Science and Technology, First People's Hospital of Yunnan, Kunming, China
| | - Shaobo Wang
- PET/CT Center, Affiliated Hospital of Kunming University of Science and Technology, First People's Hospital of Yunnan, Kunming, China
| |
Collapse
|
48
|
Weng X, Huang Y, Fu Z, Liu X, Xie F, Wang J, Zhu Q, Zheng D. METTL1-driven nucleotide metabolism reprograms the immune microenvironment in hepatocellular carcinoma: a multi-omics approach for prognostic biomarker discovery. Front Immunol 2025; 16:1582203. [PMID: 40330476 PMCID: PMC12052905 DOI: 10.3389/fimmu.2025.1582203] [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: 02/24/2025] [Accepted: 03/31/2025] [Indexed: 05/08/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, partly due to an incomplete understanding of the metabolic and immune dysregulation driving its progression. Here, we uncover a novel role of METTL1 in driving nucleotide metabolism reprogramming, which significantly modulates the tumor immune microenvironment. Methods Utilizing an integrated multi-omics approach, we analyzed nucleotide metabolism-related genes derived from TCGA, GEO, and ICGC datasets. Non-negative matrix factorization (NMF) clustering stratified HCC patients into distinct subgroups with varied clinical features. Weighted Gene Co-expression Network Analysis (WGCNA) identified hub genes that were subsequently used to construct robust prognostic models via multiple machine learning algorithms. These computational findings were validated through in vitro experiments, immune infiltration assessments, and single-cell RNA sequencing analysis. Results Our analyses demonstrate that METTL1 is markedly upregulated in HCC, driving a reprogramming of nucleotide metabolism that modulates the expression of key immune checkpoints, including PD-L1 and CTLA-4. This regulation is associated with an immunosuppressive tumor microenvironment, reduced infiltration of activated T cells, and poorer clinical outcomes. Moreover, the prognostic model integrating METTL1 expression and immune checkpoint profiles shows strong predictive performance across independent cohorts, highlighting its potential clinical utility. Conclusion This study highlights the innovative role of METTL1-driven nucleotide metabolism reprogramming in reshaping the immune microenvironment of HCC. The findings provide novel insights into HCC pathogenesis and pave the way for developing personalized therapeutic strategies based on targeting METTL1 and its associated metabolic pathways.
Collapse
Affiliation(s)
- Xie Weng
- Department of Oncology, Shunde Hospital, Southern Medical University, The First People’s Hospital of Shunde, Foshan, China
| | - Yangyue Huang
- Hepatic Department, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Zhuoya Fu
- Hepatic Department, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xingli Liu
- Department of Oncology, Shunde Hospital, Southern Medical University, The First People’s Hospital of Shunde, Foshan, China
| | - Fuli Xie
- Department of Oncology, Shunde Hospital, Southern Medical University, The First People’s Hospital of Shunde, Foshan, China
| | - Jiale Wang
- Department of Oncology, Shunde Hospital, Southern Medical University, The First People’s Hospital of Shunde, Foshan, China
| | - Qiaohua Zhu
- Department of Oncology, Shunde Hospital, Southern Medical University, The First People’s Hospital of Shunde, Foshan, China
| | - Dayong Zheng
- Department of Oncology, Shunde Hospital, Southern Medical University, The First People’s Hospital of Shunde, Foshan, China
- Hepatic Department, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| |
Collapse
|
49
|
Liao L, Yi Q, Zhao Z, Xu M, Wu T, Chen S, Liu Y. miR-6844/HSD17B13 Axis Contributes the Malignant Phenotype of Hepatocellular Carcinoma Cells. Cell Biol Int 2025. [PMID: 40255210 DOI: 10.1002/cbin.70025] [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: 12/04/2024] [Revised: 04/03/2025] [Accepted: 04/09/2025] [Indexed: 04/22/2025]
Abstract
Hepatocellular carcinoma (HCC) is a prevalent form of primary liver cancer, and aberrant miRNAs expression significantly contributes to its progression. Although the abnormal expression of miR-6844 in HCC has been reported, its impact on the malignant phenotype of HCC cells and its potential mechanism remains unclear. In this study, we initially conducted a bioinformatics analysis to investigate the differential expression of miR-6844 in HCC tissues and its impact on patient prognosis. The association between miR-6844 expression levels and clinical characteristics of HCC patients was subsequently investigated by integrating data from clinical samples. Ultimately, the impact of miR-6844 on the malignant phenotype of HCC cells and the underlying mechanisms were examined through in vitro cellular experiments. The results showed that a high expression of miR-6844 in HCC, which was associated with poor prognosis and exhibited significant correlations with intrahepatic metastasis and clinical stage among patients. The upregulation of miR-6844 promoted the proliferation, migration, and invasion of HCC cells while suppressing apoptosis. Conversely, the downregulation of miR-6844 significantly attenuated the malignant phenotype of HCC cells. In addition, HSD17B13 was identified as a target gene of miR-6844, and the overexpression of HSD17B13 partially counteracted the oncogenic effects induced by miR-6844 in HCC cells, otherwise the opposite. Taken together, the above results suggest that miR-6844 plays a regulatory role in the malignant phenotype of HCC cells through its targeting of HSD17B13.
Collapse
Affiliation(s)
- Li Liao
- Department of Hepatobiliary Surgery, Yueyang Central Hospital, Yueyang, Hunan, People's Republic of China
| | - Qilin Yi
- Department of Hepatobiliary Surgery, Yueyang Central Hospital, Yueyang, Hunan, People's Republic of China
| | - Zhen Zhao
- Department of Hepatobiliary Surgery, Yueyang Central Hospital, Yueyang, Hunan, People's Republic of China
| | - Ming Xu
- Department of Hepatobiliary Surgery, Yueyang Central Hospital, Yueyang, Hunan, People's Republic of China
| | - Tao Wu
- Department of Hepatobiliary Surgery, Yueyang Central Hospital, Yueyang, Hunan, People's Republic of China
| | - Shuai Chen
- Department of Hepatobiliary Surgery, Yueyang Central Hospital, Yueyang, Hunan, People's Republic of China
| | - Yu Liu
- Department of Hepatobiliary Surgery, Yueyang Central Hospital, Yueyang, Hunan, People's Republic of China
| |
Collapse
|
50
|
Liu G, Kuang S, Zhong W, Yang A, Huang X, Xie Y, Zhang X, Li Y, Qin Q, Liu G. Exploring the potential mechanisms of Jinglinzi powder in treating hepatocellular carcinoma based on LC-MS, network pharmacology, molecular docking, and experimental validation. J Pharm Biomed Anal 2025; 263:116899. [PMID: 40286672 DOI: 10.1016/j.jpba.2025.116899] [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: 11/21/2024] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025]
Abstract
This study systematically predicts the active components, targets, and mechanisms of JLZP against HCC by integrating LC-MS, network pharmacology, and molecular docking, with experimental validation of its pro-pyroptotic effects. Through HERB and NPASS databases, 81 bioactive components of JLZP and 78 overlapping HCC-related targets were identified. Protein-protein interaction network and KEGG enrichment analyses revealed that JLZP likely induces cell death via cancer-related pathways. Molecular docking (CB-Dock2) demonstrated high binding affinity between JLZP core components (e.g., protopine) and pyroptosis-associated targets (NLRP3, GSDMD). In vitro experiments confirmed that JLZP significantly suppressed MHCC-97L cell proliferation and migration, while upregulating pyroptosis markers (IL-1β, IL-18) at both mRNA and protein levels, with these effects reversed by a pyroptosis inhibitor. This study is the first to elucidate JLZP's anti-HCC mechanism through pyroptosis activation, identifying its pharmacodynamic material basis and multi-target action. The "component-target-pathway-experiment" multidimensional strategy provides methodological insights for deciphering traditional Chinese medicine formulas, offering a theoretical foundation for developing JLZP-based anticancer therapies.
Collapse
Affiliation(s)
- Gaofeng Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Shanshan Kuang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Weixing Zhong
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Anming Yang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510510, China
| | - Xiaoli Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yin Xie
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Xin Zhang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou 510510, China
| | - Yikai Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Qingguang Qin
- Department of acupuncture and moxibustion, Hainan Provincial People's Hospital, Haikou 570311, China.
| | - Guangjie Liu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510510, China.
| |
Collapse
|