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Liu Z, Guo Y, Zhang Y, Gao Y, Ning B. Metabolic reprogramming of astrocytes: Emerging roles of lactate. Neural Regen Res 2026; 21:421-432. [PMID: 39688570 DOI: 10.4103/nrr.nrr-d-24-00776] [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: 07/16/2024] [Accepted: 10/25/2024] [Indexed: 12/18/2024] Open
Abstract
Lactate serves as a key energy metabolite in the central nervous system, facilitating essential brain functions, including energy supply, signaling, and epigenetic modulation. Moreover, it links epigenetic modifications with metabolic reprogramming. Nonetheless, the specific mechanisms and roles of this connection in astrocytes remain unclear. Therefore, this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system. The close relationship between epigenetic modifications and metabolic reprogramming was discussed. Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases. In the nervous system, lactate plays an essential role. However, its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation. The involvement of lactate in epigenetic modifications is currently a hot research topic, especially in lactylation modification, a key determinant in this process. Lactate also indirectly regulates various epigenetic modifications, such as N6-methyladenosine, acetylation, ubiquitination, and phosphorylation modifications, which are closely linked to several neurological disorders. In addition, exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.
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Affiliation(s)
- Zeyu Liu
- Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Yijian Guo
- Department of Spinal Surgery, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Ying Zhang
- Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Yulei Gao
- Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Bin Ning
- Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
- Department of Spinal Surgery, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
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2
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Cheng Y, Guo L. Lactate metabolism and lactylation in kidney diseases: insights into mechanisms and therapeutic opportunities. Ren Fail 2025; 47:2469746. [PMID: 40012230 PMCID: PMC11869332 DOI: 10.1080/0886022x.2025.2469746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 02/10/2025] [Accepted: 02/10/2025] [Indexed: 02/28/2025] Open
Abstract
The kidney is essential for lactate metabolism. Under normal conditions, the renal cortex mainly absorbs and metabolizes lactate, with minimal amounts excreted in urine. This process is part of a glucose-lactate recycling system between the cortex and medulla. In conditions such as acute kidney injury (AKI) and diabetic kidney disease (DKD), the kidney's ability to metabolize lactate is impaired, leading to lactate accumulation and exacerbated renal dysfunction. Novel post-translational modifications, such as lactylation, are critical in kidney disease pathophysiology by modulating gene transcription, protein function, and cellular metabolism. Lactylation is involved in inflammatory responses and tumor promotion in AKI, mitochondrial dysfunction in DKD, and tumor progression in clear cell renal cell carcinoma (ccRCC). The lactate-lactylation axis is central to the Warburg effect in ccRCC, where tumor cells preferentially rely on glycolysis rather than oxidative phosphorylation. Understanding the mechanisms of lactate metabolism and lactylation in kidney diseases may offer new therapeutic strategies. This review examines the role of lactate esters, especially lactylation, in kidney diseases, with a focus on their regulatory mechanisms and potential as therapeutic targets.
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Affiliation(s)
- Yuhua Cheng
- Department of Nephrology, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
| | - Linjuan Guo
- Department of Cardiology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
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Shi Y, Liu J, Cheng Q, Wu S, Song W, Wang K, Chen Z, Li X, Wei Q, Tayier D, Liao B, Yang Z. METTL3/IGF2BP3 mediates ORC6 via N6-methyladenosine modification to promote the progression of pancreatic ductal adenocarcinoma. Gene 2025; 955:149468. [PMID: 40185346 DOI: 10.1016/j.gene.2025.149468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/19/2025] [Accepted: 03/31/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is recognized globally as one of the most lethal tumours, and effective biomarkers to diagnose PDAC early are needed. ORC6, a subunit of the origin recognition complex (ORC), initiates DNA replication and ensures genomic stability. Previous studies have indicated that ORC6 is procarcinogenic in various cancers, yet its role in PDAC remains uninvestigated. METHODS We evaluated the relationships between ORC6 expression and the clinical features of patients with PDAC with the TCGA, GTEx, and GEO databases. The role of ORC6 in PDAC cells was explored by RNA interference in vitro and in vivo. Next, we verified the effect of the METTL3/IGF2BP3/ORC6 axis on PDAC progression by western blotting, RT-qPCR, RNA immunoprecipitation, and methylated RNA immunoprecipitation. Finally, transcriptome analysis was performed to explore the influence of ORC6 on p53 in PDAC cells. RESULTS Elevated ORC6 levels were observed in PDAC cells, which correlated with poorer clinical outcomes. Both in vivo and in vitro experiments demonstrated that ORC6 knockdown suppressed proliferation and promoted apoptosis. Additionally, we demonstrated that METTL3/IGF2BP3 interacted with ORC6 mRNA via N6-methyladenosine modification to improve ORC6 mRNA stability. Transcriptomic analysis and experiments indicated that ORC6 promoted PDAC progression by inhibiting serine-15 phosphorylation in p53. CONCLUSION Our findings validate the role of ORC6 in PDAC and support the hypothesis that the METTL3/IGF2BP3/ORC6/p53 axis may be a novel therapeutic target for PDAC, and inhibiting this axis may be an advantageous therapeutic strategy for curing PDAC.
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Affiliation(s)
- Yang Shi
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Junwei Liu
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China
| | - Qian Cheng
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Shuaihui Wu
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Wenjing Song
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Kunlei Wang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Zhinan Chen
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Xinyin Li
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Qifeng Wei
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Dilinigeer Tayier
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China
| | - Bo Liao
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China.
| | - Zhiyong Yang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Pancreatic Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan 430061 Hubei Province, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430061 Hubei Province, China.
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Chen W, Wang P, Xie Y, Xie D, Wang H, Bu N, Lin J, Wu M, Xia H, Cheng C, Zhou Y, Liu Q. Histone lactylation-augmented IRF4 is implicated in arsenite-induced liver fibrosis via modulating Th17 cell differentiation. Chem Biol Interact 2025; 414:111507. [PMID: 40209842 DOI: 10.1016/j.cbi.2025.111507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 01/10/2025] [Accepted: 04/08/2025] [Indexed: 04/12/2025]
Abstract
Arsenic, a ubiquitous environmental toxicant, has been implicated in causing liver fibrosis through chronic exposure. Histone lactylation is involved in various inflammatory diseases, among which liver fibrosis is included, and is also closely related to the regulation of immune cells. This work focuses on the mechanisms of histone lactylation and Th17 cell differentiation in arsenite-induced liver fibrosis through animal and cellular experiments. Chronic arsenite exposure of mice led to liver fibrosis, elevated glycolysis in liver, and increased lactate levels in both serum and liver, which promoted Th17 cell differentiation of CD4+ T cells and increased IL-17A secretion. Treatment with oxamate, a lactate dehydrogenase inhibitor, suppressed Th17 cell differentiation and alleviated fibrosis in the liver. For HepG2 cells, arsenite exposure enhanced glycolysis and lactate levels, leading to increased global lactylation (Kla), H3K18la, interferon-regulatory factor 4 (IRF4), retinoic acid receptor-related orphan receptor gamma t (RORγt), and IL-17A expression and secretion in co-cultured Jurkat cells. Furthermore, in Jurkat cells, reducing lactate production and transport decreased these protein levels, suppressed Th17 cell differentiation, decreased IL-17A secretion, and ultimately inhibited the activation of hepatic stellate cells (HSCs). These results indicate that lactate derived from hepatocytes promotes Th17 cell differentiation by upregulating IRF4 through H3K18la, thereby enhancing IL-17A secretion and the activation of HSCs, contributing to arsenite-induced liver fibrosis. Our work reveals a new mechanism of histone lactylation in arsenite-induced liver fibrosis and offers a fresh perspective for the development of strategies for prevention and treatment of this condition.
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Affiliation(s)
- Weiyong Chen
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Peiwen Wang
- Laboratory of Modern Environmental Toxicology, Environment and Health Research Division, Public Health School and Health Research Centre, Department of Public Health and Preventive Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, People's Republic of China
| | - Yan Xie
- School of Public Health, Zunyi Medical University; Key Laboratory of Maternal and Child Health and Exposure Science, Guizhou Provincial Department of Education, Zunyi, 563060, Guizhou, People's Republic of China
| | - Daxiao Xie
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Hailan Wang
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Ning Bu
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Jiaheng Lin
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Meng Wu
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Haibo Xia
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Cheng Cheng
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China
| | - Yuanzhong Zhou
- School of Public Health, Zunyi Medical University; Key Laboratory of Maternal and Child Health and Exposure Science, Guizhou Provincial Department of Education, Zunyi, 563060, Guizhou, People's Republic of China.
| | - Qizhan Liu
- Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China.
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5
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Zhu X, Pang X, Wang X, Guan X, Tang Y, Wang Z, Zhang L, Zheng X, Li F, Mei J, Ou L, Liu Y, Meng Z, Chen Y, Ma C. Super-Enhancer-Driven LncRNA UNC5B-AS1 Inhibits Inflammatory Phenotypic Transition in Pulmonary Artery Smooth Muscle Cells via Lactylation. Arterioscler Thromb Vasc Biol 2025. [PMID: 40336475 DOI: 10.1161/atvbaha.124.322174] [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: 11/14/2024] [Accepted: 04/22/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND The phenotypic transition of pulmonary artery smooth muscle cells (PASMCs) is a central pathological alteration in pulmonary artery remodeling, contributing to pulmonary hypertension. Super-enhancers (SEs), characterized by histone modifications and the binding of coactivators, drive the expression of prominent genes that define cellular identity. However, the specific role of SEs, particularly SE-driven long noncoding RNAs, in hypoxia-induced phenotypic plasticity of PASMCs remains unclear. METHODS In this study, the long noncoding RNA UNC5B antisense RNA 1 (UNC5B-AS1) regulated by SEs was screened in hypoxic PASMCs using RNA sequencing and H3K27ac (histone 3 lysine 27 acetylation) chromatin immunoprecipitation sequencing. Overexpression or knockdown of UNC5B-AS1 in vitro was performed to elucidate its role in pulmonary hypertension pathogenesis. A serotype 5 adenovirus-associated virus carrying a conserved functional fragment of UNC5B-AS1 was used to treat pulmonary hypertension in vivo. RESULTS We identified UNC5B-AS1 as an SE-driven long noncoding RNA transcriptionally activated by the transcription factor FOXP3 (forkhead box protein P3), which regulates phenotypic transition in PASMCs. Notably, we demonstrated that UNC5B-AS1 interacts with key glycolytic enzymes in the cytoplasm and likely serves as a molecular scaffold for LRPPRC (leucine-rich PPR motif-containing protein) and oxidative respiratory chain complex IV in mitochondria. Consequently, the deficiency of UNC5B-AS1 in PASMCs promotes the lactylation of promoter regions within inflammatory genes, including those of IL (interleukin)-1β, IL-6, and TNF-α (tumor necrosis factor-α), under hypoxic conditions, ultimately leading to inflammatory phenotypic transition of PASMCs. CONCLUSIONS Our findings identify SE-driven UNC5B-AS1 as a novel regulatory factor in the hypoxia-induced phenotypic transition of PASMCs and suggest that overexpression of UNC5B-AS1 may represent a promising therapeutic strategy for pulmonary hypertension.
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Affiliation(s)
- Xiangrui Zhu
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Xiangming Pang
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Xiaoying Wang
- College of Pharmacy, Harbin Medical University (Daqing), PR China. (X.W.)
| | - Xiaoyu Guan
- College of Pharmacy, Harbin Medical University, PR China (X.G.)
| | - Yujing Tang
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Zhaosi Wang
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Lixin Zhang
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Xiaodong Zheng
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Fei Li
- College of Basic Medicine, Harbin Medical University (Daqing), PR China. (F.L.)
| | - Jian Mei
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Langlin Ou
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Yuxiang Liu
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Zitong Meng
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Yingli Chen
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
| | - Cui Ma
- College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing), PR China. (X. Zhu, X.P., Y.T., Z.W., L.Z., X. Zheng, J.M., L.O., Y.L., Z.M., Y.C., C.M.)
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Fujian Branch of National Clinical Research Center for Cardiovascular Diseases, PR China (C.M.)
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6
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Zhang X, Tang Y, Wang J, Yang M, Jiang J, Xue H, Wang Y, Zhang J, Wang X. Heat stress enhances the expression of METTL3 to mediate N6-methyladenosine modification of SOS2 and NLRP3 inflammasome activation in boar Sertoli cells. JOURNAL OF HAZARDOUS MATERIALS 2025; 488:137432. [PMID: 39884044 DOI: 10.1016/j.jhazmat.2025.137432] [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: 11/05/2024] [Revised: 01/14/2025] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Heat stress negatively affects pig production by disrupting the immune homeostasis of Sertoli cells (SCs), which compromises sperm quality, culminating in male infertility. Herein, we aimed to study the mechanism by which the NLRP3 inflammasome is activated by heat stress through N6-methyladenosine (m6A) modification regulation in SCs. Initially, it was found that heat stress (44°C, 30 min) markedly activated ERK1/2 signaling, which subsequently promoted NLRP3 inflammasome activation and inflammatory cytokine release from SCs. Then, using an m6A dot-blot assay, m6A sequencing, and methylated RNA immunoprecipitation, we found that heat stress augmented the level of m6A modification in SCs, and METTL3 augmented the m6A modification of mRNA encoding SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), a key activator of the ERK pathway. Furthermore, YTHDF1 recognized and bound to the m6A-modified SOS2 mRNA to enhance its translation efficiency, ultimately triggering ERK1/2 signaling activation. In vivo experiments demonstrated that heat stress-induced decline in semen quality in mice was associated with elevated levels of m6A modifications in the testis and NLRP3 inflammasome activation. However, the damage caused by heat stress could be attenuated by intraperitoneal injection of S-Adenosylhomocysteine (SAH), a specific methyltransferase inhibitor. Our results emphasize the critical roles of m6A in regulating NLRP3 inflammasome activation under heat stress, identifying a novel therapeutic avenue to address heat stress.
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Affiliation(s)
- Xuhua Zhang
- Chongqing Key Laboratory of Forage & Herbivore, College of Veterinary Medicine, Southwest University, Beibei, Chongqing 400715, PR China
| | - Yan Tang
- Chongqing Key Laboratory of Forage & Herbivore, College of Veterinary Medicine, Southwest University, Beibei, Chongqing 400715, PR China
| | - Jinxuan Wang
- Chongqing Key Laboratory of Forage & Herbivore, College of Veterinary Medicine, Southwest University, Beibei, Chongqing 400715, PR China
| | - Mengyu Yang
- Chongqing Key Laboratory of Forage & Herbivore, College of Veterinary Medicine, Southwest University, Beibei, Chongqing 400715, PR China
| | - Jing Jiang
- Chongqing Key Laboratory of Forage & Herbivore, College of Veterinary Medicine, Southwest University, Beibei, Chongqing 400715, PR China
| | - Hongyan Xue
- Chongqing Key Laboratory of Forage & Herbivore, College of Veterinary Medicine, Southwest University, Beibei, Chongqing 400715, PR China
| | - Yi Wang
- Department of Biomedical Engineering, Faculty of Engineering and Information Technology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Jiaojiao Zhang
- Chongqing Key Laboratory of Forage & Herbivore, College of Veterinary Medicine, Southwest University, Beibei, Chongqing 400715, PR China.
| | - Xianzhong Wang
- Chongqing Key Laboratory of Forage & Herbivore, College of Veterinary Medicine, Southwest University, Beibei, Chongqing 400715, PR China.
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7
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Chen C, Wang J, Zhu X, Zhang S, Yuan X, Hu J, Liu C, Liu L, Zhang Z, Li J. Lactylation as a metabolic epigenetic modification: Mechanistic insights and regulatory pathways from cells to organs and diseases. Metabolism 2025:156289. [PMID: 40324589 DOI: 10.1016/j.metabol.2025.156289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/20/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
In recent years, lactylation, a novel post-translational modification, has demonstrated a unique role in bridging cellular metabolism and epigenetic regulation. This modification exerts a dual-edged effect in both cancer and non-cancer diseases by dynamically integrating the supply of metabolic substrates and the activity of modifying enzymes: on one hand, it promotes tissue homeostasis and repair through the activation of repair genes; on the other, it exacerbates pathological progression by driving malignant phenotypes. In the field of oncology, lactylation regulates key processes such as metabolic reprogramming, immune evasion, and therapeutic resistance, thereby shaping the heterogeneity of the tumor microenvironment. In non-cancerous diseases, including neurodegeneration and cardiovascular disorders, its aberrant activation can lead to mitochondrial dysfunction, fibrosis, and chronic inflammation. Existing studies have revealed a dynamic regulatory network formed by the cooperation of modifying and demodifying enzymes, and have identified mechanisms such as subcellular localization and RNA metabolism intervention that influence disease progression. Nevertheless, several challenges remain in the field. This article comprehensively summarizes the disease-specific regulatory mechanisms of lactylation, with the aim of providing a theoretical foundation for its targeted therapeutic application.
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Affiliation(s)
- Cong Chen
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Jie Wang
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China.
| | - Xueying Zhu
- Department of Anatomy, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shan Zhang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xiandun Yuan
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100096, China
| | - Jun Hu
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Chao Liu
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Lanchun Liu
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China
| | - Zhenpeng Zhang
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China.
| | - Jun Li
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, Beijing 100053, China.
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8
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Li D, Liu Z, Zhu M, Yu W, Mao W, Mao D, Wang F, Wan Y. Histone lactylation regulates early embryonic development through m6A methyltransferase METTL3 in goats. Int J Biol Macromol 2025; 309:142858. [PMID: 40216110 DOI: 10.1016/j.ijbiomac.2025.142858] [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: 02/18/2025] [Revised: 03/31/2025] [Accepted: 04/03/2025] [Indexed: 04/15/2025]
Abstract
Histone lysine lactylation (Kla) is a novel epigenetic modification that plays a crucial role in cellular processes driven by glycolysis and lactate production. However, the mechanisms of histone lactylation and its interaction with m6A RNA methylation during early embryonic development remain underexplored. This study systematically investigated the effects of oxygen levels-atmospheric oxygen (atmosO2; 20% O2) and physiological oxygen (physO2; 5% O2)-on hallmark events during early embryonic development, revealing that lactylation modification regulates early goat embryonic development through the m6A methyltransferase-like 3 (METTL3). We observed that physO2 conditions significantly promote embryonic development, with higher expression levels of METTL3, global histone lactylation, and histone H3 lysine 18 lactylation (H3K18la) compared to atmosO2 exposure. Furthermore, the addition of lactate dehydrogenase inhibitors led to a decrease in global lactylation, which was accompanied by a significant reduction in METTL3 expression. Sequencing analysis of the METTL3 knockdown embryo revealed that the differentially expressed genes (DEGs) were primarily enriched in the ribosome, oxidative phosphorylation, thermogenesis, RNA degradation, and RNA polymerase pathways. These findings provide novel insights into the epigenetic regulatory mechanisms of histone lactylation during early embryonic development in livestock, highlighting potential molecular targets and strategies to enhance mammalian in vitro embryo production techniques.
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Affiliation(s)
- Dongxu Li
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Zifei Liu
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Minghui Zhu
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Wenyue Yu
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Weijia Mao
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Dagan Mao
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Feng Wang
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Yongjie Wan
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
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9
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Zhang J, Lin F, Xu Y, Sun J, Zhang L, Chen W. Lactylation and Ischemic Stroke: Research Progress and Potential Relationship. Mol Neurobiol 2025; 62:5359-5376. [PMID: 39541071 DOI: 10.1007/s12035-024-04624-4] [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: 04/20/2024] [Accepted: 11/09/2024] [Indexed: 11/16/2024]
Abstract
Ischemic stroke is caused by interrupted cerebral blood flow and is a leading cause of mortality and disability worldwide. Significant advancements have been achieved in comprehending the pathophysiology of stroke and the fundamental mechanisms responsible for ischemic damage. Lactylation, as a newly discovered post-translational modification, has been reported to participate in several physiological and pathological processes. However, research on lactylation and ischemic stroke is scarce. This review summarized the current function of protein lactylation in other diseases or normal physiological processes and explored their potential link with the pathophysiological process and the reparative mechanism of ischemic stroke. We proposed that neuroinflammation, regulation of metabolism, regulation of messenger RNA translation, angiogenesis, and neurogenesis might be the bridge linking lactylation and ischemic stroke. Our study provided a novel perspective for comprehending the role of protein lactylation in the pathophysiological processes underlying ischemic stroke. Lactylation might be a promising target in drug development of ischemic stroke.
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Affiliation(s)
- Jingyuan Zhang
- Department of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Feng Lin
- Department of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Yue Xu
- Department of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Jiaxin Sun
- Department of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Lei Zhang
- Department of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China.
| | - Wenli Chen
- Department of Pharmacy, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, China.
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10
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Cai J, Zhang P, Cai Y, Zhu G, Chen S, Song L, Du J, Wang B, Dai W, Zhou J, Fan J, Yu Y, Dai Z. Lactylation-Driven NUPR1 Promotes Immunosuppression of Tumor-Infiltrating Macrophages in Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2413095. [PMID: 40305758 DOI: 10.1002/advs.202413095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 04/13/2025] [Indexed: 05/02/2025]
Abstract
While checkpoint immunotherapy effectively mobilizes T-cell responses against tumors, its success in hepatocellular carcinoma (HCC) is frequently undermined by immunosuppressive myeloid cells within the tumor microenvironment. This study investigates the role of nuclear protein 1 (NUPR1), a gene prominently expressed in tumor-associated macrophages (TAMs), in mediating this suppression and influencing immunotherapy outcomes. Through comprehensive analysis of single-cell RNA sequencing (scRNA-seq) datasets and functional assays in vitro and in vivo, NUPR1 is identified as a critical regulator within TAMs. The upregulation of NUPR1 is associated with enhanced M2 macrophage polarization and increased expression of immune checkpoints PD-L1 and SIRPA, resulting in CD8+ T cell exhaustion and a diminished response to immunotherapy. Mechanistically, NUPR1 inhibits the ERK and JNK signaling pathways, thereby creating an immunosuppressive milieu conducive to tumor progression. Additionally, tumor-derived lactate is shown to upregulate NUPR1 expression in macrophages via histone lactylation, perpetuating a feedback loop that intensifies immune suppression. Pharmacological targeting of NUPR1 reverses M2 polarization, curtails tumor growth, and augments the efficacy of PD-1 blockade in preclinical models, positioning NUPR1 as both a potential biomarker for immunotherapy responsiveness and a therapeutic target to boost immunotherapy efficacy in HCC.
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Affiliation(s)
- Jialiang Cai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
| | - Peiling Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
| | - Yufan Cai
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Guiqi Zhu
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, 100000, China
| | - Shiping Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
| | - Lina Song
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
| | - Junxian Du
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Biao Wang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Weixing Dai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, 100000, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, 100000, China
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
- Cancer Center, Zhongshan Hospital Fudan University, Shanghai, 200032, China
| | - Zhi Dai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China
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11
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Gao C, Li J, Shan B. Research progress on the regulatory role of lactate and lactylation in tumor microenvironment. Biochim Biophys Acta Rev Cancer 2025; 1880:189339. [PMID: 40311713 DOI: 10.1016/j.bbcan.2025.189339] [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: 11/27/2024] [Revised: 04/26/2025] [Accepted: 04/28/2025] [Indexed: 05/03/2025]
Abstract
The tumor microenvironment (TME) arises from the dynamic interactions between tumor cells and the surrounding medium, including a variety of cell types and extracellular components, which have an important impact on the genesis and development of tumors. A key player in TME is lactate, a metabolic byproduct of glycolysis, which serves as a significant energy source. Lactate has direct implications on the survival and differentiation of immune cells, the metabolic reprogramming and progression of tumor cells. Moreover, lactylation, a unique post-translational modification, exerts a regulatory effect on TME by affecting gene transcription via adding lactate groups to both histone and non-histone proteins. This review systematically and comprehensively synthesizes emerging evidence on how the lactate-lactylation axis drives immune evasion, therapy resistance, and TME remodeling, highlighting the therapeutic targets related to lactate and lactylation that dismantle this metabolic-epigenetic crosstalk.
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Affiliation(s)
- Chunyan Gao
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Prevention, Precision Diagnosis and Treatment of Hebei, Clinical Oncology Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - Jiali Li
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Prevention, Precision Diagnosis and Treatment of Hebei, Clinical Oncology Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - Baoen Shan
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Prevention, Precision Diagnosis and Treatment of Hebei, Clinical Oncology Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China.
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12
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Qiao Y, Liu Y, Ran R, Zhou Y, Gong J, Liu L, Zhang Y, Wang H, Fan Y, Fan Y, Nan G, Zhang P, Yang J. Lactate metabolism and lactylation in breast cancer: mechanisms and implications. Cancer Metastasis Rev 2025; 44:48. [PMID: 40295451 PMCID: PMC12037681 DOI: 10.1007/s10555-025-10264-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 04/06/2025] [Indexed: 04/30/2025]
Abstract
As the end-product of glycolysis, lactate serves as a regulator of protein lactylation in addition to being an energy substrate, metabolite, and signaling molecule in cancer. The reprogramming of glucose metabolism and the Warburg effect in breast cancer results in extensive lactate production and accumulation, making it likely that lactylation in tumor tissue is also abnormal. This review summarizes evidence on lactylation derived from studies of lactate metabolism and disease, highlighting the role of lactate in the tumor microenvironment of breast cancer and detailing the levels of lactylation and cancer-promoting mechanisms across various tumors. The roles of lactate and lactylation, along with potential intervention mechanisms, are presented and discussed, offering valuable insights for future research on the role of lactylation in tumors.
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Affiliation(s)
- Yifan Qiao
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yijia Liu
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ran Ran
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yan Zhou
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jin Gong
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lijuan Liu
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yusi Zhang
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hui Wang
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuan Fan
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yihan Fan
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Gengrui Nan
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Peng Zhang
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China.
- Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China.
| | - Jin Yang
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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13
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Li Y, Cao Y, He L, Wu J, Cai L, Zhou Y, Li H, Yang W, Sun T. Cisplatin reduces immunosuppression caused by tumor-associated macrophages through downregulating CD47-SIRPα signaling in glioblastoma. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167876. [PMID: 40300658 DOI: 10.1016/j.bbadis.2025.167876] [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: 10/11/2024] [Revised: 03/08/2025] [Accepted: 04/25/2025] [Indexed: 05/01/2025]
Abstract
The poor prognosis of glioblastoma (GBM) is partly attributed to the immunosuppressive microenvironment. The combination of standard temozolomide and other chemotherapy drugs can significantly enhance the therapeutic effect by reshaping the immune microenvironment. Cisplatin treatment induces immunogenic cell death in tumor cells, stimulating an immune response. Here, we investigated the immune-activating effect of cisplatin on tumor-associated macrophages (TAMs). The therapeutic benefit of temozolomide plus cisplatin was showed in a murine model of GBM, accompanied by the inhibition of tumor growth and enhancement of pro-inflammatory activation of TAMs. Furthermore, cisplatin treatment downregulated the expression of CD47 in glioma stem cells, SIRPα, and IL-6 in TAMs, thus promoting M1-like polarization of TAMs to enhance an immune-activating tumor microenvironment. Mechanically, cisplatin decreases the production of lactic acid by downregulating LDHA expression. A low level of lactate reduces histone H3K18 lactylation on the CD47 and IL-6 promoters, thereby suppressing gene transcription. Our study reveals a new mechanism by which cisplatin remodels the immune tumor microenvironment, suggesting that combining temozolomide with cisplatin chemotherapy may be a new treatment option for GBM.
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Affiliation(s)
- Yanyan Li
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yufei Cao
- Department of Critical Care Medicine, Affiliated First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Linyan He
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Nhc Key Laboratory of Thrombosis and Hemostasis, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jie Wu
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Lize Cai
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Youxin Zhou
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Haiying Li
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Wei Yang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, China.
| | - Ting Sun
- Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
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14
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Rao K, Zhang X, Luo Y, Xia Q, Jin Y, He J. Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth. Cell Rep 2025; 44:115441. [PMID: 40106438 DOI: 10.1016/j.celrep.2025.115441] [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: 07/12/2024] [Revised: 01/06/2025] [Accepted: 02/26/2025] [Indexed: 03/22/2025] Open
Abstract
Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradation of cyclic GMP-AMP synthase (cGAS) independent of ubiquitin, thus repressing the production of interferon and contributing to tumor growth. Mechanistically, lactylation of K21 stimulates cGAS translocation from the nucleus to the proteasome for degradation, which is compromised by phosphorylation of PSMA4 S188 via disrupting its association with cGAS. Concurrently, lactylation of K415 rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4 S188. Physiologically, lactylation of cGAS sustains tumor growth. Expression of cGAS correlates with the antitumor effect of the LDHA inhibitor FX11. Finally, the lactate-cGAS axis indicates a prognostic outcome of lung adenocarcinoma. Collectively, these findings not only put forth a mechanism of cGAS degradation but also unravel the clinical relevance of cGAS lactylation.
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Affiliation(s)
- Keqiang Rao
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China
| | - Xinchao Zhang
- Department of Pathology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China.
| | - Yuting Jin
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China.
| | - Jing He
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China.
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15
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Xing Z, Yang T, Li X, Xu H, Hong Y, Shao S, Li T, Ye L, Li Y, Jin X, Wei Y. High-glucose-associated YTHDC1 lactylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy. Cell Rep 2025; 44:115545. [PMID: 40215164 DOI: 10.1016/j.celrep.2025.115545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 01/26/2025] [Accepted: 03/19/2025] [Indexed: 04/26/2025] Open
Abstract
Hyperglycemia is a recognized risk factor for bladder cancer (BC). Enfortumab vedotin (EV), the first NECTIN4-targeting antibody-drug conjugate, demonstrates promising clinical efficacy in patients with advanced BC. In this study, we show that EV treatment is less effective in BC patients with diabetes than in those with normoglycemia. The subsequent in vitro and in vivo experiments indicate that high glucose decreases the sensitivity of BC cells to EV. Mechanistically, lactate overproduction associated with high glucose promotes AARS1-mediated YTHDC1 lactylation and enhances RNF183-mediated YTHDC1 ubiquitination. Downregulated YTHDC1 reduces JUND mRNA stability in an m6A-dependent manner, subsequently decreasing NECTIN4 expression and EV responsiveness. Our study identifies a high-glucose-associated lactate-AARS1-YTHDC1-JUND-NECTIN4 axis that affects EV sensitivity in BC. Targeting this axis with JUND activators or β-alanine may offer therapeutic strategies to enhance the sensitivity of BC cells to EV.
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Affiliation(s)
- Zhuo Xing
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Tiejun Yang
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Xurui Li
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Haozhe Xu
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yulong Hong
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Shuai Shao
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Tao Li
- Shengli Clinical Medical College of Fujian Medical University, Department of Urology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, No. 134, Dong Street, Fuzhou 350001, People's Republic of China
| | - Liefu Ye
- Shengli Clinical Medical College of Fujian Medical University, Department of Urology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, No. 134, Dong Street, Fuzhou 350001, People's Republic of China
| | - Yuan Li
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
| | - Xin Jin
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; FuRong Laboratory, Changsha 410078, Hunan, China.
| | - Yongbao Wei
- Shengli Clinical Medical College of Fujian Medical University, Department of Urology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, No. 134, Dong Street, Fuzhou 350001, People's Republic of China.
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16
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Sun Y, Wang H, Cui Z, Yu T, Song Y, Gao H, Tang R, Wang X, Li B, Li W, Wang Z. Lactylation in cancer progression and drug resistance. Drug Resist Updat 2025; 81:101248. [PMID: 40287994 DOI: 10.1016/j.drup.2025.101248] [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: 03/20/2025] [Revised: 04/15/2025] [Accepted: 04/18/2025] [Indexed: 04/29/2025]
Abstract
Lactate plays a crucial role as an energy substrate, metabolite, and signaling molecule in cancer. Lactate has long been considered a byproduct of glycolysis. Still, the lactate shuttle hypothesis has changed the lactate paradigm, revealing the implications of lactate in cellular metabolism and cellular communications that can transcend the compartment barrier and occur within and between different cells, tissues, and organs. Due to the Warburg effect, the tumor produces a large amount of lactate, thus creating a low-nutrition, hypoxic, and low-pH tumor microenvironment (TME). Consequently, immunosuppressive networks are built to acquire immune evasion potential and regulate tumor growth. Lactylation is a newly discovered post-translational modification of lysine residues with the capacity for transcriptional regulation via histone modification and modulation of non-histone protein functions, which links gene regulation to cellular metabolism by aberrant metabolism activity and epigenetic modification. There is growing evidence that lactylation plays a crucial role in cancer progression and drug resistance. Targeting lactylation enzymes or metabolic pathways has shown promising effects in suppressing cancer progression and drug resistance, highlighting the therapeutic potential of this modification. Therefore, in this review, we offer a systematic overview of lactate homeostasis in physiological and pathological processes as well as discuss the influence of lactylation in cancer progression and drug resistance and underlying molecular mechanisms, providing a theoretical basis for further research.
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Affiliation(s)
- Yuxiu Sun
- Department of Digestive Diseases 1, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - He Wang
- Department of Breast Medicine 2, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Zhe Cui
- Laboratory Department, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Tingting Yu
- Department of Gynecology Surgery 4, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Yuanming Song
- Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Haolai Gao
- First Clinical College, Liaoning University of Traditional Chinese Medicine Affiliated Hospital, Liaoning Provincial Traditional Chinese Medicine Hospital, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, China
| | - Ruihong Tang
- Medical Equipment Department, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Xinlei Wang
- Department of Interventional Therapy, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Binru Li
- Department of Thoracic Medicine 2, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China.
| | - Wenxin Li
- Second Ward of Hepatobiliary and Pancreatic Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China.
| | - Zhe Wang
- Department of Digestive Diseases 1, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China.
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Li H, Ren Q, Shi M, Ma L, Fu P. Lactate metabolism and acute kidney injury. Chin Med J (Engl) 2025; 138:916-924. [PMID: 38802283 PMCID: PMC12037090 DOI: 10.1097/cm9.0000000000003142] [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: 01/22/2024] [Indexed: 05/29/2024] Open
Abstract
ABSTRACT Acute kidney injury (AKI) is a common clinically critical syndrome in hospitalized patients with high morbidity and mortality. At present, the mechanism of AKI has not been fully elucidated, and no therapeutic drugs exist. As known, glycolytic product lactate is a key metabolite in physiological and pathological processes. The kidney is an important gluconeogenic organ, where lactate is the primary substrate of renal gluconeogenesis in physiological conditions. During AKI, altered glycolysis and gluconeogenesis in kidneys significantly disturb the lactate metabolic balance, which exert impacts on the severity and prognosis of AKI. Additionally, lactate-derived posttranslational modification, namely lactylation, is novel to AKI as it could regulate gene transcription of metabolic enzymes involved in glycolysis or Warburg effect. Protein lactylation widely exists in human tissues and may severely affect non-histone functions. Moreover, the strategies of intervening lactate metabolic pathways are expected to bring a new dawn for the treatment of AKI. This review focused on renal lactate metabolism, especially in proximal renal tubules after AKI, and updated recent advances of lactylation modification, which may help to explore potential therapeutic targets against AKI.
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Affiliation(s)
- Hui Li
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Qian Ren
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Min Shi
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Liang Ma
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Ping Fu
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
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18
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Zhao J, Li L, Wang Y, Huo J, Wang J, Xue H, Cai Y. Identification of gene signatures associated with lactation for predicting prognosis and treatment response in breast cancer patients through machine learning. Sci Rep 2025; 15:13575. [PMID: 40253524 PMCID: PMC12009422 DOI: 10.1038/s41598-025-98255-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 04/10/2025] [Indexed: 04/21/2025] Open
Abstract
As a newly discovered histone modification, abnormal lactation has been found to be present in and contribute to the development of various cancers. The aim of this study was to investigate the potential role between lactylation and the prognosis of breast cancer patients. Lactylation-associated subtypes were obtained by unsupervised consensus clustering analysis. Lactylation-related gene signature (LRS) was constructed by 15 machine learning algorithms, and the relationship between LRS and tumor microenvironment (TME) as well as drug sensitivity was analyzed. In addition, the expression of genes in the LRS in different cells was explored by single-cell analysis and spatial transcriptome. The expression levels of genes in LRS in clinical tissues were verified by RT-PCR. Finally, the potential small-molecule compounds were analyzed by CMap, and the molecular docking model of proteins and small-molecule compounds was constructed. LRS was composed of 6 key genes (SHCBP1, SIM2, VGF, GABRQ, SUSD3, and CLIC6). BC patients in the high LRS group had a poorer prognosis and had a TME that promoted tumor progression. Single-cell analysis and spatial transcriptome revealed differential expression of the key genes in different cells. The results of PCR showed that SHCBP1, SIM2, VGF, GABRQ, and SUSD3 were up-regulated in the cancer tissues, whereas CLIC6 was down-regulated in the cancer tissues. Arachidonyltrifluoromethane, AH-6809, W-13, and clofibrate can be used as potential target drugs for SHCBP1, VGF, GABRQ, and SUSD3, respectively. The gene signature we constructed can well predict the prognosis as well as the treatment response of BC patients. In addition, our predicted small-molecule complexes provide an important reference for personalized treatment of breast cancer patients.
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Affiliation(s)
- Jinfeng Zhao
- College of Physical Education, Shanxi University, Taiyuan, Shanxi, China
| | - Longpeng Li
- College of Physical Education, Shanxi University, Taiyuan, Shanxi, China
| | - Yaxin Wang
- College of Physical Education, Shanxi University, Taiyuan, Shanxi, China
| | - Jiayu Huo
- College of Physical Education, Shanxi University, Taiyuan, Shanxi, China
| | - Jirui Wang
- College of Physical Education, Shanxi University, Taiyuan, Shanxi, China
| | - Huiwen Xue
- College of Physical Education, Shanxi University, Taiyuan, Shanxi, China
| | - Yue Cai
- Department of Anesthesiology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical, Taiyuan, Shanxi, China.
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19
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Sun Y, Yang X, Kong F, Dong FY, Li N, Wang S. The mechanisms and effects of lactylation modification in different kinds of cancers. Discov Oncol 2025; 16:560. [PMID: 40249419 PMCID: PMC12008107 DOI: 10.1007/s12672-025-02359-9] [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: 12/27/2024] [Accepted: 04/09/2025] [Indexed: 04/19/2025] Open
Abstract
Lactylation, a recently identified post-translational modification, has garnered significant attention for its associations with various diseases, particularly its critical role in tumor progression and treatment. It is emerging as a potential clinical target. The elevated metabolic activity of cancer cells often leads to excessive lactate accumulation, a phenomenon termed the "Warburg effect", which is a hallmark of the tumor microenvironment. Recent research reveals that lactate is not merely a metabolic byproduct but also serves as a substrate for protein lactylation, influencing tumor development by regulating cellular signaling, gene expression, and immune responses. This dual role has become a focal point for scientists and clinicians seeking novel therapeutic strategies targeting lactate-related pathways. Despite growing interest, the detailed mechanisms and therapeutic applications of lactylation across different cancer types remain inadequately explored. This review synthesizes current findings on lactylation mechanisms in various tumors, highlights potential therapeutic targets, and offers new perspectives to advance cancer treatment.
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Affiliation(s)
- Yixun Sun
- College of Clinical Medicine, Jining Medical University, Jining, 272007, Shandong, China
| | - Xiaxia Yang
- Department of Laboratory Medicine,, Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Jining, 272000, Shandong, China
| | - Feifei Kong
- Department of Laboratory Medicine,, Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Jining, 272000, Shandong, China
| | - Feng Yun Dong
- Department of Laboratory Medicine,, Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Jining, 272000, Shandong, China
| | - Na Li
- Department of Pediatrics, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272007, Shandong, China
| | - Sen Wang
- Department of Laboratory Medicine,, Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Jining, 272000, Shandong, China.
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20
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Ma P, Wang R, Chen H, Zheng J, Yang W, Meng B, Liu Y, Lu Y, Zhao J, Gao H. Fecal microbiota transplantation alleviates lipopolysaccharide-induced osteoporosis by modulating gut microbiota and long non-coding RNA TUG1 expression. Front Cell Infect Microbiol 2025; 15:1535666. [PMID: 40292220 PMCID: PMC12021831 DOI: 10.3389/fcimb.2025.1535666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 03/28/2025] [Indexed: 04/30/2025] Open
Abstract
Purpose To study whether fecal microbiota transplantation (FMT) can alleviate lipopolysaccharide (LPS)-induced osteoporosis (OP) by regulating the composition and abundance of gut microbiota and the expression level of long non-coding RNA (lncRNA) TUG1. Methods Twenty C57BL/6 mice were selected. Two mice were randomly designated as fecal donors, while the remaining mice were randomly divided into control group, LPS group, and LPS + FMT group. Each group consisted of 6 mice. The mice in the LPS and LPS + FMT groups were intraperitoneally injected with LPS to establish the OP model, and the mice in the LPS + FMT group were treated with donor feces by gavage. Micro-CT was used to scan the femur specimens of mice, and the bone structural parameters of the control and LPS groups were compared to verify the effectiveness of the OP model. HE staining was used to compare the microstructure of femurs in the 3 groups. 16S rRNA gene sequencing was used to analyze the composition and abundance of gut microbiota in mice. Immunofluorescence staining was used to compare the expression levels of Runt-related transcription factor 2 (RUNX2) in the femur of the 3 groups. Real-time quantitative reverse transcription PCR (qRT-PCR) was used to compare the expression levels of lncRNA TUG1 in the intestines and serum of mice in the 3 groups. Results Micro-CT showed that compared with the control group, the mice in the LPS group had more bone loss. The bone mineral density, trabecular number, and trabecular thickness of the control group was higher, and the trabecular separation was smaller. The models were validated effectively. HE staining showed that compared with the control group, the bone trabeculae in the LPS group were thinner and sparse, while that in the LPS + FMT group were dense and clear. The 16s rRNA sequencing showed that the abundance of Bacteroides and Lactobacillus in LPS+FMT group was significantly higher than that in LPS group. Immunofluorescence staining showed that the RUNX2 level in the control group and LPS + FMT group was similar, and both were higher than that in the LPS group. The qRT-PCR results showed that the TUG1 mRNA level in the control group and LPS + FMT group was similar and significantly higher than that in the LPS group. Conclusion FMT can enhance osteoblast levels and improve bone structure by modulating the abundance of gut microbiota in OP mice (such as increasing Bacteroides and Lactobacillus populations) and promoting the expression of lncRNA TUG1, thereby alleviating LPS-induced OP.
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Affiliation(s)
- Pengcheng Ma
- Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Ruoyi Wang
- Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Huizhi Chen
- Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Jiachun Zheng
- Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Weijie Yang
- Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Bo Meng
- Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Yifan Liu
- Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Yao Lu
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Jing Zhao
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China
| | - Hongwei Gao
- Shandong Public Health Clinical Center, Shandong University, Jinan, China
- School of Mechanical Engineering, Shandong University, Jinan, China
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21
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Zhang Y, Zhao J, Li J, Li Y, Jiang L, Wang N. Functions of Tomato ( Solanum lycopersicum L.) Signal Transducer and Activator of Transcription (STAT) in Seed Germination and Low-Temperature Stress Response. Int J Mol Sci 2025; 26:3338. [PMID: 40244180 PMCID: PMC11989334 DOI: 10.3390/ijms26073338] [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: 02/18/2025] [Revised: 03/27/2025] [Accepted: 03/31/2025] [Indexed: 04/18/2025] Open
Abstract
Tomato (Solanum lycopersicum L.) is one of the major vegetable crops worldwide. Research on the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway in tomatoes and other plant systems is extremely limited. In this study, the roles of STAT, a crucial element of the JAK-STAT signaling pathway in tomato seed germination and low-temperature stress responses are examined, employing gene family analysis and genetic transformation. The results indicate that the S. lycopersicum genome contains only one member of the STAT gene family, SlSTAT. Subcellular localization experiments reveal that SlSTAT is found in both the cytoplasm and nucleus, suggesting its potential involvement in biological functions within these cellular compartments. Among the 26 different tomato tissue/organs tested, SlSTAT exhibited higher expression levels in hypocotyl (8 days past germination; 8 DPG), and low expression of SlSTAT significantly reduced the germination rate and impacted biomass at 8 DPG. In addition, the SlSTAT gene was significantly downregulated during low-temperature treatment. Compared with the wild-type (WT) tomatoes, the SlSTAT-overexpressing plants showed more resistance to low-temperature conditions, whereas the downexpressing tomatoes exhibited increased sensitivity. The expressions of low-temperature marker genes (SlCBF1-3) and N6-methyladenosine (m6A)-modification-related genes (m6A writer, reader, and eraser genes) were detected to explore possible molecular mechanisms by which SlSTAT causes changes in tomato low-temperature stress resistance. The expression changes of SlCBF1-3 in transgenic plants do not merely follow a straightforward linear relationship with the changes in SlSTAT expression, suggesting a more complex molecular mechanism and a non-direct interaction between SlSTAT and the promoters of SlCBFs. On the other hand, SlSTAT also changes the expression levels of RNA m6A-modification-related genes, especially SlFIP37 (writer gene), SlYTP8/9 (reader genes), and SlALKBH8 (eraser gene), ultimately leading to changes in the levels of m6A modification. These research findings lay the groundwork for exploring functions of JAK-STAT pathway in tomato development and stress responses, expanding the scope of JAK-STAT signaling studies in plant systems.
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Affiliation(s)
| | | | | | | | | | - Na Wang
- College of Life Sciences and Medicine, Shandong University of Technology, Zibo 255000, China
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22
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Iozzo M, Pardella E, Giannoni E, Chiarugi P. The role of protein lactylation: A kaleidoscopic post-translational modification in cancer. Mol Cell 2025; 85:1263-1279. [PMID: 40073861 DOI: 10.1016/j.molcel.2025.02.011] [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: 10/15/2024] [Revised: 12/18/2024] [Accepted: 02/14/2025] [Indexed: 03/14/2025]
Abstract
The recently discovered lysine lactylation represents a critical post-translational modification with widespread implications in epigenetics and cancer biology. Initially identified on histones, lysine lactylation has been also described on non-histone proteins, playing a pivotal role in transcriptional activation, protein function, and cellular processes. Two major sources of the lactyl moiety have been currently distinguished: L-lactyl-CoA (precursor of the L-lactyl moiety) and S-D-lactylglutathione (precursor of the D-lactyl moiety), which enable enzymatic and non-enzymatic mechanisms of lysine lactylation, respectively. Although the specific writers, erasers, and readers of this modification are still unclear, acetyltransferases and deacetylases have been proposed as crucial mediators of lysine lactylation. Remarkably, lactylation exerts significant influence on critical cancer-related pathways, thereby shaping cellular behavior during malignant transformation and the metastatic cascade. Hence, as recent insights into lysine lactylation underscore its growing potential in tumor biology, targeting this modification is emerging as a significant opportunity for cancer treatment.
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Affiliation(s)
- Marta Iozzo
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Elisa Pardella
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Elisa Giannoni
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Paola Chiarugi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
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23
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Zhu Z, Zheng X, Zhao P, Chen C, Xu G, Ke X. Potential of lactylation as a therapeutic target in cancer treatment (Review). Mol Med Rep 2025; 31:91. [PMID: 39950331 PMCID: PMC11836599 DOI: 10.3892/mmr.2025.13456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/24/2025] [Indexed: 02/21/2025] Open
Abstract
Post‑translational modifications (PTMs) of proteins influence their functionality by altering the structure of precursor proteins. These modifications are closely linked to tumor progression through the regulation of processes such as cell proliferation, apoptosis, angiogenesis and invasion. Tumors produce large amounts of lactic acid through aerobic glycolysis. Lactic acid not only serves an important role in cell metabolism, but also serves an important role in cell communication. Lactylation, a PTM involving lactate and lysine residues as substrates, serves as an epigenetic regulator that modulates intracellular signaling, gene expression and protein function, thereby serving a crucial role in tumorigenesis and progression. The identification of lactylation provides a key breakthrough in elucidating the interaction between tumor metabolic reprogramming and epigenetic modification. The present review primarily summarizes the occurrence of lactylation, its effect on tumor progression, drug resistance, the tumor microenvironment and gut microbiota, and its potential as a therapeutic target for cancer. The aim of the present review was to provide novel strategies for potential cancer therapies.
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Affiliation(s)
- Zhengfeng Zhu
- Department of Clinical Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Xinzhe Zheng
- Department of Clinical Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Pengfei Zhao
- Department of Clinical Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Cheng Chen
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Gang Xu
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Xixian Ke
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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24
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Zhang W, Shan G, Bi G, Hu Z, Yi Y, Zeng D, Lin Z, Zhan C. Lactylation and regulated cell death. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119927. [PMID: 40023198 DOI: 10.1016/j.bbamcr.2025.119927] [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: 11/27/2024] [Revised: 02/11/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025]
Abstract
Lactylation, a newly identified post-translational modification, entails the attachment of lactate to lysine residues within proteins, profoundly modulating diverse cellular mechanisms underlying regulated cell death (RCD). This modification encompasses two primary categories: histone lactylation and non-histone lactylation. Histone lactylation assumes a pivotal regulatory function in the RCD process, primarily by modulating the transcriptional landscape of genes implicated in cell death. In contrast, non-histone lactylation exerts its influence by targeting transferases, transcription, cell cycle progression, death pathways, and metabolic processes that are intricately involved in RCD. This review provides a comprehensive overview of recent breakthroughs in understanding how lactylation regulates RCD, while also offering insights into potential avenues for future research, thereby deepening our comprehension of cellular fate determination.
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Affiliation(s)
- Wenlong Zhang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Guangyao Shan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Guoshu Bi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Zhengyang Hu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Yanjun Yi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Dejun Zeng
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Zongwu Lin
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China.
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai 200032, China.
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25
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Zhu W, Zeng S, Zhu S, Zhang Z, Zhao R, Qiu Q, Luo Z, Qin Y, Chen W, Li B, He Y, Yi L, Ding H, Zhao M, Chen J, Fu C, Fan S. Histone H2B lysine lactylation modulates the NF-κB response via KPNA2 during CSFV infection. Int J Biol Macromol 2025; 299:139973. [PMID: 39826749 DOI: 10.1016/j.ijbiomac.2025.139973] [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: 08/08/2024] [Revised: 12/23/2024] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
Histone lysine lactylation (Kla) has recently been reported to participate in various biological processes, regulating transcription, inflammation, and immune-related diseases. However, the mechanism of histone Kla in innate immunity and viral infection remains largely unknown. Here, we observed fluorescent Kla signals in all four histones (H2A, H2B, H3, and H4) in PK-15 cells. Immunoprecipitation analysis showed prominent histone Kla protein bands, with H2B being the most abundant. We generated the H2B K16R mutant plasmid and identified K16 as one of the Kla modification sites in H2B. Further exploration revealed increased global H2B Kla and H2BK16la levels upon classical swine fever virus (CSFV) infection. By employing the Kla agonist (L-lactate), inhibitor (oxamate), or siLDHA, we demonstrated that H2BK16la and pan Kla in PK-15 cells rely on the LDHA-lactate axis, which is also crucial for CSFV-induced H2BK16la and pan Kla levels. Moreover, our data proved the interaction between H2B and CSFV NS4A protein. Notably, H2B Kla can modulate CSFV proliferation. Mechanistically, H2BK16la and pan Kla activate the nuclear factor kappa B (NF-κB) pathway by mediating p65 nuclear translocation via karyopherin α2 (KPNA2), thereby inducing type III interferon (IFN-λ) expression and inhibiting CSFV replication. In conclusion, our study unveils the role of H2B Kla in regulating the NF-κB pathway during viral infection, presenting a novel mechanism. These findings significantly contribute to understanding the pathogenic mechanisms during viral infection and hold promise for the development of viral therapeutic strategies.
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Affiliation(s)
- Wenhui Zhu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Sen Zeng
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Shuaiqi Zhu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Zhanhui Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Ruibo Zhao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Qi Qiu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Zipeng Luo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Yuwei Qin
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Wenxian Chen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Bingke Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Yintao He
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Lin Yi
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou 510642, China
| | - Hongxing Ding
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou 510642, China
| | - Mingqiu Zhao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou 510642, China
| | - Jinding Chen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou 510642, China.
| | - Cheng Fu
- College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China.
| | - Shuangqi Fan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou 510642, China; Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, PR China.
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He X, Li Y, Li J, Li Y, Chen S, Yan X, Xie Z, Du J, Chen G, Song J, Mei Q. HDAC2-Mediated METTL3 Delactylation Promotes DNA Damage Repair and Chemotherapy Resistance in Triple-Negative Breast Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413121. [PMID: 39950833 PMCID: PMC11984901 DOI: 10.1002/advs.202413121] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/09/2025] [Indexed: 04/12/2025]
Abstract
The current treatment of triple-negative breast cancer (TNBC) is still primarily based on platinum-based chemotherapy. However, TNBC cells frequently develop resistance to platinum and experience relapse after drug withdrawal. It is crucial to specifically target and eliminate cisplatin-tolerant cells after platinum administration. Here, it is reported that upregulated N 6-methyladenosine (m6A) modification drives the development of resistance in TNBC cells during cisplatin treatment. Mechanistically, histone deacetylase 2 (HDAC2) mediates delactylation of methyltransferase-like 3 (METTL3), facilitating METTL3 interaction with Wilms'-tumor-1-associated protein and subsequently increasing m6A of transcript-associated DNA damage repair. This ultimately promotes cell survival under cisplatin. Furthermore, pharmacological inhibition of HDAC2 using Tucidinostat can enhance the sensitivity of TNBC cells to cisplatin therapy. This study not only elucidates the biological function of lactylated METTL3 in tumor cells but also highlights its negative regulatory effect on cisplatin resistance. Additionally, it underscores the nonclassical functional mechanism of Tucidinostat as a HDAC inhibitor for improving the efficacy of cisplatin against TNBC.
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Affiliation(s)
- Xiaoniu He
- Shanxi Bethune HospitalShanxi Academy of Medical SciencesThird Hospital of Shanxi Medical UniversityTongji Shanxi HospitalTaiyuan030032China
| | - Yuanpei Li
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060China
| | - Jian Li
- Institute of Molecular Medicine and Experimental ImmunologyUniversity Clinic of Rheinische Friedrich‐Wilhelms‐University53127BonnGermany
| | - Yu Li
- Department of Human Cell Biology and GeneticsJoint Laboratory of Guangdong‐Hong Kong Universities for Vascular Homeostasis and DiseasesSchool of MedicineSouthern University of Science and TechnologyShenzhen518055China
| | - Sijie Chen
- Department of Human Cell Biology and GeneticsJoint Laboratory of Guangdong‐Hong Kong Universities for Vascular Homeostasis and DiseasesSchool of MedicineSouthern University of Science and TechnologyShenzhen518055China
| | - Xia Yan
- Shanxi Bethune HospitalShanxi Academy of Medical SciencesThird Hospital of Shanxi Medical UniversityTongji Shanxi HospitalTaiyuan030032China
| | - Zhangrong Xie
- Department of Human Cell Biology and GeneticsJoint Laboratory of Guangdong‐Hong Kong Universities for Vascular Homeostasis and DiseasesSchool of MedicineSouthern University of Science and TechnologyShenzhen518055China
| | - Jiangfeng Du
- Department of Medical ImagingShanxi Key Laboratory of Intelligent Imaging and NanomedicineFirst Hospital of Shanxi Medical UniversityTaiyuan030001China
| | - Guoan Chen
- Department of Human Cell Biology and GeneticsJoint Laboratory of Guangdong‐Hong Kong Universities for Vascular Homeostasis and DiseasesSchool of MedicineSouthern University of Science and TechnologyShenzhen518055China
| | - Jianbo Song
- Shanxi Bethune HospitalShanxi Academy of Medical SciencesThird Hospital of Shanxi Medical UniversityTongji Shanxi HospitalTaiyuan030032China
| | - Qi Mei
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
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27
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Zhao L, Guo J, Xu S, Duan M, Liu B, Zhao H, Wang Y, Liu H, Yang Z, Yuan H, Jiang X, Jiang X. Abnormal changes in metabolites caused by m 6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application. J Adv Res 2025; 70:159-186. [PMID: 38677545 PMCID: PMC11976433 DOI: 10.1016/j.jare.2024.04.016] [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: 02/18/2024] [Revised: 04/14/2024] [Accepted: 04/14/2024] [Indexed: 04/29/2024] Open
Abstract
BACKGROUND N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor. AIM OF REVIEW The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations. KEY SCIENTIFIC CONCEPTS OF REVIEW This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.
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Affiliation(s)
- Liang Zhao
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; Department of Colorectal Anal Surgery, Shenyang Coloproctology Hospital, Shenyang 110002, China.
| | - Junchen Guo
- Department of Radiology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Shasha Xu
- Department of Gastroendoscopy, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Meiqi Duan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Baiming Liu
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - He Zhao
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Yihan Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Haiyang Liu
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Zhi Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Hexue Yuan
- Department of Colorectal Anal Surgery, Shenyang Coloproctology Hospital, Shenyang 110002, China.
| | - Xiaodi Jiang
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang 110020, China.
| | - Xiaofeng Jiang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
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28
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Ren H, Tang Y, Zhang D. The emerging role of protein L-lactylation in metabolic regulation and cell signalling. Nat Metab 2025; 7:647-664. [PMID: 40175761 DOI: 10.1038/s42255-025-01259-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 03/03/2025] [Indexed: 04/04/2025]
Abstract
L-Lactate has emerged as a crucial metabolic intermediate, moving beyond its traditional view as a mere waste product. The recent discovery of L-lactate-driven protein lactylation as a post-translational modification has unveiled a pathway that highlights the role of lactate in cellular signalling. In this Perspective, we explore the enzymatic and metabolic mechanisms underlying protein lactylation and its impacts on both histone and non-histone proteins in the contexts of physiology and diseases. We discuss growing evidence suggesting that this modification regulates a wide range of cellular functions and is involved in various physiological and pathological processes, such as cell-fate determination, development, cardiovascular diseases, cancer and autoimmune disorders. We propose that protein lactylation acts as a pivotal mechanism, integrating metabolic and signalling pathways to enable cellular adaptation, and highlight its potential as a therapeutic target in various diseases.
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Affiliation(s)
- Haowen Ren
- State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing, China
| | - Yuwei Tang
- State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing, China
- Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Di Zhang
- State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing, China.
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
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29
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Yin R, Jing G, Tian Y, Ma M, Zhang M. The impact of lactate on diabetic cognitive dysfunction: Insights from energy metabolism to epigenetic modulation. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167749. [PMID: 40010229 DOI: 10.1016/j.bbadis.2025.167749] [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: 09/19/2024] [Revised: 02/15/2025] [Accepted: 02/20/2025] [Indexed: 02/28/2025]
Abstract
This manuscript elucidates the intricate roles of lactate in Diabetic Cognitive Dysfunction (DCD), extending beyond its conventional role as an energy substrate. The investigation centers on the participation of lactate in energy metabolism and epigenetic modulation, with a particular emphasis on its influence on cognitive faculties through histone lactylation. The discourse scrutinizes lactate's part in the metabolic equilibrium of the central nervous system, encompassing its fluctuating concentrations under various conditions and its pivotal function within the Astrocyte-Neuron Lactate Shuttle (ANLS) mechanism as an energy conduit. The involvement of lactate in DCD is multilayered, encompassing metabolic pathways, cellular signaling cascades, and the regulation of gene expression. Dysregulation in lactate metabolism and the histone lactylation process may modulate neuronal functionality by impacting genes integral to neuroplasticity and cognitive capabilities. These revelations offer novel insights into the molecular underpinnings of DCD and lay the groundwork for the discovery of potential therapeutic targets. Subsequent scholarly endeavors are poised to dissect the nuanced mechanisms by which lactate and its lactylation exert influence in DCD, pinpointing the critical genes modulated by lactylation and assessing their ramifications on neuronal function and signal transduction pathways. Given the intricate regulatory dynamics of lactate, contingent upon concentration, temporal factors, and disease etiology, a more profound elucidation of lactate's role in DCD necessitates an augmented cadre of animal experimentation and clinical observational research. Such investigative pursuits are anticipated to yield innovative approaches and methodologies for the comprehensive management of DCD, spanning prevention, diagnosis, and therapeutic intervention.
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Affiliation(s)
- Ruiying Yin
- Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Guangchan Jing
- Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yue Tian
- Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Mei Ma
- Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Mengren Zhang
- Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
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30
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Zong Z, Ren J, Yang B, Zhang L, Zhou F. Emerging roles of lysine lactyltransferases and lactylation. Nat Cell Biol 2025; 27:563-574. [PMID: 40185947 DOI: 10.1038/s41556-025-01635-8] [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: 04/26/2024] [Accepted: 02/13/2025] [Indexed: 04/07/2025]
Abstract
Given its various roles in cellular functions, lactate is no longer considered a waste product of metabolism and lactate sensing is a pivotal step in the transduction of lactate signals. Lysine lactylation is a recently identified post-translational modification that serves as an intracellular mechanism of lactate sensing and transfer. Although acetyltransferases such as p300 exhibit general acyl transfer activity, no bona fide lactyltransferases have been identified. Recently, the protein synthesis machinery, alanyl-tRNA synthetase 1 (AARS1), AARS2 and their Escherichia coli orthologue AlaRS, have been shown to be able to sense lactate and mediate lactyl transfer and are thus considered pan-lactyltransferases. Here we highlight the mechanisms and functions of these lactyltransferases and discuss potential strategies that could be exploited for the treatment of human diseases.
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Affiliation(s)
- Zhi Zong
- The First Affiliated Hospital of Soochow University, Suzhou, China
- Institutes of Biology and Medical Science, Soochow University, Suzhou, China
| | - Jiang Ren
- MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Institute of Biomedical Innovation, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Bing Yang
- State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of the Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
| | - Long Zhang
- MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Institute of Biomedical Innovation, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China.
- State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of the Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China.
| | - Fangfang Zhou
- The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institutes of Biology and Medical Science, Soochow University, Suzhou, China.
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31
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Xiong Q, Zhang Y, Zheng Y, Zhu Q. Regulation and application of m 6A modification in tumor immunity. SCIENCE CHINA. LIFE SCIENCES 2025; 68:974-993. [PMID: 39648245 DOI: 10.1007/s11427-024-2648-0] [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: 03/02/2024] [Accepted: 06/11/2024] [Indexed: 12/10/2024]
Abstract
The m6A modification is an RNA modification that impacts various processes of RNA molecules, including transcription, splicing, stability, and translation. Recently, researchers have discovered that the presence of m6A modification can influence the interaction between tumor cells and immune cells and also play a role in regulating the expression of immune response-related genes. Additionally, m6A modification is intricately involved in the regulation of tumor immune evasion and drug resistance. Specifically, certain tumor cells can manipulate the gene expression through m6A modification to evade immune system attacks. Therefore, it might be possible to enhance tumor immune surveillance and improve the effectiveness of immune-based therapies by manipulating m6A modification. This review systematically discusses the role of m6A modification in tumor immunity, specifically highlighting its regulation of immune cells and immune-related genes in tumor cells. Furthermore, we explore the potential of m6A modification inhibitors as anti-cancer therapies and the significance of m6A regulatory factors in predicting the efficacy of tumor immune therapy.
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Affiliation(s)
- Qunli Xiong
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yaguang Zhang
- Laboratory of Gastrointestinal Tumor Epigenetics and Genomics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ying Zheng
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qing Zhu
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
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32
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Han Z, Shen Y, Yan Y, Bin P, Zhang M, Gan Z. Metabolic reprogramming shapes post-translational modification in macrophages. Mol Aspects Med 2025; 102:101338. [PMID: 39977975 DOI: 10.1016/j.mam.2025.101338] [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: 09/11/2024] [Revised: 12/10/2024] [Accepted: 01/11/2025] [Indexed: 02/22/2025]
Abstract
Polarized macrophages undergo metabolic reprogramming, as well as extensive epigenetic and post-translational modifications (PTMs) switch. Metabolic remodeling and dynamic changes of PTMs lead to timely macrophage response to infection or antigenic stimulation, as well as its transition from a pro-inflammatory to a reparative phenotype. The transformation of metabolites in the microenvironment also determines the PTMs of macrophages. Here we reviewed the current understanding of the altered metabolites of glucose, lipids and amino acids in macrophages shape signaling and metabolism pathway during macrophage polarization via PTMs, and how these metabolites in some macrophage-associated diseases affect disease progression by shaping macrophage PTMs.
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Affiliation(s)
- Ziyi Han
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Yinhao Shen
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Yuqi Yan
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Peng Bin
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Meimei Zhang
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
| | - Zhending Gan
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China; College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China.
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33
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Sun C, Li J, Dong L, Mou Y, Zhang B, Song X. Lactylation: A Novel Epigenetic Regulator of Cellular Senescence. Aging Dis 2025:AD.2025.0277. [PMID: 40153584 DOI: 10.14336/ad.2025.0277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 03/23/2025] [Indexed: 03/30/2025] Open
Abstract
Cellular senescence is the basic unit of organismal aging, a complicated biological process involving several cell types and tissues. It is also an important mechanism by which the body responds to damage and potential carcinogenesis. However, excessive or abnormal cellular senescence can lead to tissue functional degradation and the occurrence of diseases. In recent years, the role of epigenetic modifications in cellular senescence has received extensive attention. Lactylation, a novel post-translational modification derived from lactate, has recently gained significant attention as a key factor in cellular metabolism and epigenetic regulation, gradually demonstrating its importance in the regulation of cellular senescence. This review emphasizes the bidirectional causal relationship between lactylation and cellular senescence, highlighting its potential as a therapeutic target for aging-related diseases.
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Affiliation(s)
- Caiyu Sun
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, China
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China
| | - Jiaxuan Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China
| | - Lei Dong
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China
| | - Yakui Mou
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China
| | - Bei Zhang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Xicheng Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, China
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34
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Gu XY, Yang JL, Lai R, Zhou ZJ, Tang D, Hu L, Zhao LJ. Impact of lactate on immune cell function in the tumor microenvironment: mechanisms and therapeutic perspectives. Front Immunol 2025; 16:1563303. [PMID: 40207222 PMCID: PMC11979165 DOI: 10.3389/fimmu.2025.1563303] [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: 01/19/2025] [Accepted: 03/10/2025] [Indexed: 04/11/2025] Open
Abstract
Lactate has emerged as a key regulator in the tumor microenvironment (TME), influencing both tumor progression and immune dynamics. As a byproduct of aerobic glycolysis, lactate satisfies the metabolic needs of proliferating tumor cells while reshaping the TME to facilitate immune evasion. Elevated lactate levels inhibit effector immune cells such as CD8+ T and natural killer cells, while supporting immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, thus fostering an immunosuppressive environment. Lactate promotes epigenetic reprogramming, stabilizes hypoxia-inducible factor-1α, and activates nuclear factor kappa B, leading to further immunological dysfunction. In this review, we examined the role of lactate in metabolic reprogramming, immune suppression, and treatment resistance. We also discuss promising therapeutic strategies targeting lactate metabolism, including lactate dehydrogenase inhibitors, monocarboxylate transporter inhibitors, and TME neutralization methods, all of which can restore immune function and enhance immunotherapy outcomes. By highlighting recent advances, this review provides a theoretical foundation for integrating lactate-targeted therapies into clinical practice. We also highlight the potential synergy between these therapies and current immunotherapeutic strategies, providing new avenues for addressing TME-related challenges and improving outcomes for patients with cancer.
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Affiliation(s)
- Xuan-Yu Gu
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jia-Li Yang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Rui Lai
- Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zheng-Jun Zhou
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Dan Tang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Hepatobiliary and Pancreatic Surgery, Suzhou Medical College of Soochow University, Suzhou, China
| | - Long Hu
- Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China
| | - Li-Jin Zhao
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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35
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Zhou J, Wang R, Zhang Z, Xue Y. METTL3 regulated by histone lactylation promotes ossification of the ligamentum flavum by enhancing the m6A methylation of BMP2. Mol Med 2025; 31:118. [PMID: 40133819 PMCID: PMC11938755 DOI: 10.1186/s10020-025-01173-x] [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: 09/25/2024] [Accepted: 03/18/2025] [Indexed: 03/27/2025] Open
Abstract
Ossification of the ligamentum flavum (OLF) is characterized by ligamentum flavum thickening and subsequent thoracic canal stenosis. Emerging evidence has demonstrated the involvement of N6-methyladenosine (m6A) methylation in OLF pathogenesis. This study investigates the regulatory role of METTL3-mediated m6A methylation of BMP2 in OLF progression. Clinical ligamentum flavum tissues were analyzed for m6A levels using dot blot analysis. Osteogenic differentiation was assessed through quantitative real-time PCR (qPCR), alkaline phosphatase staining, alizarin red S staining, and western blot analysis. Mechanistic insights were obtained through methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and luciferase reporter assays. The regulatory role of histone lactylation on METTL3 expression was examined using LDHA knockdown, sodium lactate (Nala) treatment, and 2-deoxy-D-glucose (2-DG) administration in OLF cells. Our findings revealed significant upregulation of METTL3 expression and m6A levels in OLF patients. METTL3 was shown to enhance osteogenic differentiation and m6A methylation of BMP2, which was specifically recognized by IGF2BP1. Furthermore, increased histone lactylation was observed in OLF patients, with enrichment in the METTL3 promoter region facilitating its transcriptional activation. LDHA knockdown-mediated inhibition of endogenous lactylation suppressed osteogenic differentiation, a phenotype that was rescued by METTL3 overexpression. In conclusion, this study elucidates that histone lactylation-mediated upregulation of METTL3 promotes OLF progression through IGF2BP1-dependent m6A methylation of BMP2, providing novel insights into potential therapeutic strategies for OLF management.
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Affiliation(s)
- Jiaming Zhou
- Department of Orthopaedic Surgery, Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Medical University General Hospital, Tianjin, China
| | - Rui Wang
- Department of Orthopaedic Surgery, Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Medical University General Hospital, Tianjin, China
| | - Zequn Zhang
- Department of Orthopaedic Surgery, Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuan Xue
- Department of Orthopaedic Surgery, Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Medical University General Hospital, Tianjin, China.
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36
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Deng J, Li Y, Yin L, Liu S, Li Y, Liao W, Mu L, Luo X, Qin J. Histone lactylation enhances GCLC expression and thus promotes chemoresistance of colorectal cancer stem cells through inhibiting ferroptosis. Cell Death Dis 2025; 16:193. [PMID: 40113760 PMCID: PMC11926133 DOI: 10.1038/s41419-025-07498-z] [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: 09/18/2024] [Revised: 02/10/2025] [Accepted: 03/03/2025] [Indexed: 03/22/2025]
Abstract
Colorectal cancer stem cells (CCSCs) play a critical role in mediating chemoresistance. Lactylation is a post-translational modification induced by lactate that regulates gene expression. However, whether lactylation affects the chemoresistance of CCSCs remains unknown. Here, we demonstrate that histone lactylation enhances CCSC chemoresistance both in vitro and in vivo. Furthermore, our findings showed that p300 catalyzes the lactylation of histone H4 at K12, whereas HDAC1 facilitates its delactylation in CCSCs. Notably, lactylation at H4K12 (H4K12la) upregulates GCLC expression and inhibits ferroptosis in CCSCs, and the inhibition of p300 or LDHA decreases H4K12la levels, thereby increasing the chemosensitivity of CCSCs. Additionally, the GCLC inhibitor BSO promotes ferroptosis and sensitizes CCSCs to oxaliplatin. Taken together, these findings suggest that histone lactylation upregulates GCLC to inhibit ferroptosis signaling, thus enhancing CCSC chemoresistance. These findings provide new insights into the relationship between cellular metabolism and chemoresistance and suggest potential therapeutic strategies targeting p300, LDHA, and GCLC. We showed that histones H4K12 lactylation promoted chemoresistance in CSCs. p300 catalyzes the lactylation of histone H4 at K12, HDAC1 inhibits the histone lactylation at the same site. H4K12la in CSCs regulates the expression of the ferroptosis-related gene GCLC, thereby inhibiting ferroptosis and leading to chemoresistance. Targeting the p300, LDHA, or GCLC may be overcome tumor chemoresistance.
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Affiliation(s)
- Jiao Deng
- Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yangkun Li
- Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lanlan Yin
- Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shuang Liu
- Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Yanqi Li
- Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wancheng Liao
- Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lei Mu
- Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xuelai Luo
- Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jichao Qin
- Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- Department of Gastrointestinal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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Yi D, Zhou K, Pan Y, Cai H, Huang P. The lactylation modification of proteins plays a critical role in tumor progression. Front Oncol 2025; 15:1530567. [PMID: 40190564 PMCID: PMC11970033 DOI: 10.3389/fonc.2025.1530567] [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: 01/01/2025] [Accepted: 03/04/2025] [Indexed: 04/09/2025] Open
Abstract
Lactylation modifications have been shown to be a novel type of protein post-translational modifications (PTMs), providing a new perspective for understanding the interaction between cellular metabolic reprogramming and epigenetic regulation. Studies have shown that lactylation plays an important role in the occurrence, development, angiogenesis, invasion and metastasis of tumors. It can not only regulate the phenotypic expression and functional polarization of immune cells, but also participate in the formation of tumor drug resistance through a variety of molecular mechanisms. In this review, we review the latest research progress of lactylation modification in tumors, focusing on its mechanism of action in angiogenesis, immune cell regulation in tumor microenvironment (TME), and tumor drug resistance, aiming to provide a theoretical basis and research ideas for the discovery of new therapeutic targets and methods. Through the in-depth analysis of lactylation modification, it is expected to open up a new research direction for tumor treatment and provide potential strategies for overcoming tumor drug resistance and improving clinical efficacy.
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Affiliation(s)
- Dehao Yi
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ke Zhou
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yinlong Pan
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Huazhong Cai
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Pan Huang
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China
- School of Medicine, Jiangsu University, Zhenjiang, China
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Dai J, Lu X, Zhang C, Qu T, Li W, Su J, Guo R, Yin D, Wu P, Han L, Zhang E. NNMT promotes acquired EGFR-TKI resistance by forming EGR1 and lactate-mediated double positive feedback loops in non-small cell lung cancer. Mol Cancer 2025; 24:79. [PMID: 40089784 PMCID: PMC11909984 DOI: 10.1186/s12943-025-02285-y] [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: 10/09/2024] [Accepted: 02/26/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung cancer (NSCLC). However, patients inevitably develop acquired drug resistance, resulting in recurrence or metastasis. It is important to identify novel effective therapeutic targets to reverse acquired TKI resistance. RESULTS Bioinformatics analysis revealed that nicotinamide N-methyltransferase (NNMT) was upregulated in EGFR-TKI resistant cells and tissues via EGR1-mediated transcriptional activation. High NNMT levels were correlated with poor prognosis in EGFR-mutated NSCLC patients, which could promote resistance to EGFR-TKIs in vitro and in vivo. Mechanistically, NNMT catalyzed the conversion of nicotinamide to 1-methyl nicotinamide by depleting S-adenosyl methionine (the methyl group donor), leading to a reduction in H3K9 trimethylation (H3K9me3) and H3K27 trimethylation (H3K27me3) and subsequent epigenetic activation of EGR1 and ALDH3A1. In addition, ALDH3A1 activation increased lactic acid levels, which further promoted NNMT expression via p300-mediated histone H3K18 lactylation on its promoter. Thus, NNMT mediates the formation of a double positive feedback loop via EGR1 and lactate, EGR1/NNMT/EGR1 and NNMT/ALDH3A1/lactate/NNMT. Moreover, the combination of a small-molecule inhibitor for NNMT (NNMTi) and osimertinib exhibited promising potential for the treatment of TKI resistance in an NSCLC osimertinib-resistant xenograft model. CONCLUSIONS The combined contribution of these two positive feedback loops promotes EGFR-TKI resistance in NSCLC. Our findings provide new insight into the role of histone methylation and histone lactylation in TKI resistance. The pivotal NNMT-mediated positive feedback loop may serve as a powerful therapeutic target for overcoming EGFR-TKI resistance in NSCLC.
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Affiliation(s)
- Jiali Dai
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Xiyi Lu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Chang Zhang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Tianyu Qu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Wei Li
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Jun Su
- Department of Oncology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China
| | - Renhua Guo
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Dandan Yin
- Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Zhong Fu Road, Gulou District, Nanjing, Jiangsu, 210003, PR China.
| | - Pingping Wu
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institue of Cancer Research, Nanjing, Jiangsu, PR China.
| | - Liang Han
- Department of Oncology, Xuzhou Central Hospital, Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, Jiangsu, PR China.
| | - Erbao Zhang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
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Wang FX, Mu G, Yu ZH, Shi ZA, Li XX, Fan X, Chen Y, Zhou J. Lactylation: a promising therapeutic target in ischemia-reperfusion injury management. Cell Death Discov 2025; 11:100. [PMID: 40082399 PMCID: PMC11906755 DOI: 10.1038/s41420-025-02381-4] [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: 03/02/2024] [Revised: 12/25/2024] [Accepted: 02/28/2025] [Indexed: 03/16/2025] Open
Abstract
Ischemia-reperfusion injury (IRI) is a critical condition that poses a significant threat to patient safety. The production of lactate increases during the process of IRI, and lactate serves as a crucial indicator for assessing the severity of such injury. Lactylation, a newly discovered post-translational modification in 2019, is induced by lactic acid and predominantly occurs on lysine residues of histone or nonhistone proteins. Extensive studies have demonstrated the pivotal role of lactylation in the pathogenesis and progression of various diseases, including melanoma, myocardial infarction, hepatocellular carcinoma, Alzheimer's disease, and nonalcoholic fatty liver disease. Additionally, a marked correlation between lactylation and inflammation has been observed. This article provides a comprehensive review of the mechanism underlying lactylation in IRI to establish a theoretical foundation for better understanding the interplay between lactylation and IRI.
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Affiliation(s)
- Fei-Xiang Wang
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, China
| | - Guo Mu
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
- Department of Anesthesiology, Zigong Fourth People's Hospital, Zigong, Sichuan, China
| | - Zi-Hang Yu
- Department of Anesthesiology, Fushun County People's Hospital, Zigong, Sichuan, China
| | - Zu-An Shi
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, China
| | - Xue-Xin Li
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, China
| | - Xin Fan
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, China
| | - Ye Chen
- Department of Traditional Chinese Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Jun Zhou
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China.
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, China.
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Peng TY, Lu JM, Zheng XL, Zeng C, He YH. The role of lactate metabolism and lactylation in pulmonary arterial hypertension. Respir Res 2025; 26:99. [PMID: 40075458 PMCID: PMC11905457 DOI: 10.1186/s12931-025-03163-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Pulmonary arterial hypertension (PAH) is a complex and progressive disease characterized by elevated pulmonary artery pressure and vascular remodeling. Recent studies have underscored the pivotal role of metabolic dysregulation and epigenetic modifications in the pathogenesis of PAH. Lactate, a byproduct of glycolysis, is now recognized as a key molecule that links cellular metabolism with activity regulation. Recent findings indicate that, in addition to altered glycolytic activity and dysregulated. Lactate homeostasis and lactylation-a novel epigenetic modification-also play a significant role in the development of PAH. This review synthesizes current knowledge regarding the relationship between altered glycolytic activity and PAH, with a particular focus on the cumulative effects of lactate in pulmonary vascular cells. Furthermore, lactylation, an emerging epigenetic modification, is discussed in the context of PAH. By elucidating the complex interplay between lactate metabolism and lactylation in PAH, this review aims to provide insights into potential therapeutic targets. Understanding these metabolic pathways may lead to innovative strategies for managing PAH and improving patient outcomes. Future research should focus on the underlying mechanisms through which lactylation influences the pathophysiology of PAH, thereby aiding in the development of targeted interventions.
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Affiliation(s)
- Tong-Yu Peng
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Jun-Mi Lu
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Xia-Lei Zheng
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Cheng Zeng
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Yu-Hu He
- Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
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Li J, Ma P, Liu Z, Xie J. L- and D-Lactate: unveiling their hidden functions in disease and health. Cell Commun Signal 2025; 23:134. [PMID: 40075490 PMCID: PMC11905701 DOI: 10.1186/s12964-025-02132-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/27/2025] [Indexed: 03/14/2025] Open
Abstract
Lactate, once considered a mere byproduct of anaerobic metabolism, is now recognized as a critical signaling molecule with diverse roles in physiology and pathology. There are two stereoisomers of lactate: L- and D-lactate. Recent studies have shown that disruptions in these two lactate stereoisomers have distinct effects on health and disease. L-lactate is central to glycolysis and energy transfer through the Cori cycle but also acts as the dominant lactylation isomer induced by glycolysis, influencing metabolism and cell survival. Although less studied, D-lactate is linked to metabolic disorders and plays a role in mitochondrial dysfunction and oxidative stress. This review focuses on both L- and D-lactate and examines their biosynthesis, transport, and expanding roles in physiological and pathological processes, particularly their functions in cancer, immune regulation, inflammation, neurodegeneration and other diseases. Finally, we assess the therapeutic prospects of targeting lactate metabolism, highlighting emerging strategies for intervention in clinical settings. Our review synthesizes the current understanding of L- and D-lactate, offering insights into their potential as targets for therapeutic innovation.
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Affiliation(s)
- Jianting Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, No. 56, Xinjiannan Road, Ying Ze District, Taiyuan, 030001, China
| | - Peng Ma
- Department of Anatomy, School of Basic Medical, Shanxi Medical University, Taiyuan, 030001, China
| | - Zhizhen Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, No. 56, Xinjiannan Road, Ying Ze District, Taiyuan, 030001, China
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, No. 56, Xinjiannan Road, Ying Ze District, Taiyuan, 030001, China.
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Mao Z, Li M, Wang S. Targeting m 6A RNA Modification in Tumor Therapeutics. Curr Oncol 2025; 32:159. [PMID: 40136363 PMCID: PMC11941731 DOI: 10.3390/curroncol32030159] [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: 02/05/2025] [Revised: 02/27/2025] [Accepted: 03/07/2025] [Indexed: 03/27/2025] Open
Abstract
The prevalent eukaryotic RNA modification N6-methyladenosine (m6A), which is distributed in more than 50% of cases, has demonstrated significant implications in both normal development and disease progression, particularly in the context of cancer. This review aims to discuss the potential efficacy of targeting tumor cells through modulation of m6A RNA levels. Specifically, we discuss how the upregulation or downregulation of integral or specific targets is effective in treating different tumor types and patients. Additionally, we will cover the factors influencing the efficacy of m6A RNA targeting in tumor treatment. Our review will focus on the impact of targeting m6A mRNA on genes and cells and assess its potential as a therapeutic strategy for tumors. Despite the challenges involved, further research on m6A RNA in tumors and its integration with existing tumor therapy approaches is warranted.
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Affiliation(s)
- Zhenwei Mao
- Department of Laboratory Medicine, Affiliated People’s Hospital, Jiangsu University, Zhenjiang 212002, China
- Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang 212002, China
| | - Min Li
- Department of Laboratory Medicine, Affiliated People’s Hospital, Jiangsu University, Zhenjiang 212002, China
- Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang 212002, China
| | - Shengjun Wang
- Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang 212002, China
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
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43
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Zhu Y, Fu Y, Liu F, Yan S, Yu R. Appraising histone H4 lysine 5 lactylation as a novel biomarker in breast cancer. Sci Rep 2025; 15:8205. [PMID: 40065036 PMCID: PMC11893895 DOI: 10.1038/s41598-025-92666-6] [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: 07/19/2024] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
Background Posttranslational modifications of histone lysine (K) have integral connections with cell metabolism, and participate in the carcinogenesis of various cancers. This study focuses on evaluating the expression of histone H4 lys 5 lactylation (H4K5lac) and its clinical role in breast cancer (BC). Methods During this research, immunohistochemistry (IHC) and immunoblotting, utilizing a specific primary anti-L-lactyl-histone H4 (Lys 5) rabbit monoclonal antibody, were employed to assess H4K5lac expression in BC tissue chips. H4K5lac expression in the peripheral blood mononuclear cells (PBMCs) of BC patients was investigated through immunoblotting. Results IHC revealed upregulation of histone H4K5lac in both triple-negative breast cancer (TNBC) and non-TNBC tissues, with positive rate of 91.40% [170/(150 + 19 + 17)] and 93.64% (103/110) in TNBC and non-TNBC tissues, respectively. The expression of H4K5lac demonstrated positive correlations with lymph nodes (%), and Ki-67 expression. Survival analysis indicated a negative correlation between H4K5lac expression and overall survival (OS) time in both TNBC (HR [hazard ratio] = 2.773, 95%CI [confidence interval]: 1.128-6.851, P = 0.0384) and non-TNBC cases (HR = 2.156, 95%CI: 1.011-4.599, P = 0.0275). Furthermore, elevated levels of H4K5lac were observed in the PBMCs of BC cases, and H4K5lac expression is positively correlated with serum lactate and carcinoma embryonic antigen (CEA) levels. Conclusions Histone H4K5lac exhibits increased levels in both BC tissues and PBMCs, suggesting its potential as a promising biomarker for BC. This study might pave the way toward novel lactylation treatment strategies in BC.
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Affiliation(s)
- Ya Zhu
- Department of Clinical Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450003, Henan, China
| | - Yuping Fu
- School of Medicine Laboratory, Sanquan College of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Fengzhen Liu
- Department of Clinical Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450003, Henan, China
| | - Sha Yan
- Department of Laboratory Medicine, Henan Province Hospital of TCM (the Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou, 450002, Henan, China
| | - Ruili Yu
- Department of Pathology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, 450003, Henan, China.
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44
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Liang L, Yang X, Yao S, Li X, Wang F. Identification of lactylation-associated fibroblast subclusters predicting prognosis and cancer immunotherapy response in colon cancer. Gene 2025; 940:149220. [PMID: 39765285 DOI: 10.1016/j.gene.2025.149220] [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: 08/20/2024] [Revised: 01/02/2025] [Accepted: 01/03/2025] [Indexed: 01/18/2025]
Abstract
BACKGROUND Lactylation plays an important role in tumor progression. This study aimed to clarify the impact of lactylation on cancer-associated fibroblasts(CAFs). METHODS Single-cell and bulk RNA sequence data, along with survival information, were obtained from TCGA and GEO datasets. Significant lactylation-associated genes were acquired by differential analysis and used to construct a prognostic model via Cox and LASSO regression analyses. Next, single-cell analysis, enrichment and pathway analysis, pseudotemporal trajectory and survival analysis were used to identify significant lactylation-associated fibroblast subclusters in colon cancer. IMvigor210 and PRJEB23709 cohorts were applied to assess the response to immunotherapy. In vitro experiments were conducted to explore how lactylation affect fibroblasts. RESULTS We established a lactylation-associated prognostic model with 17 risk genes in TCGA and further validated it in GEO datasets. Single-cell analysis revealed the lactylation level of fibroblasts in colon cancer was greater than that in normal tissues. Moreover, five lactylation-associated fibroblast subclusters were identified via the NMF algorithm. Patients with lower scores of FB_2_CALD1, FB_3_TPM4 and FB_4_AHNAK subclusters had better clinical prognosis in colon cancer and were more likely to benefit from immunotherapy. Further experiments demonstrated that lactylation could enhance the proliferation, migration and invasion ability of fibroblasts and up-regulate the expression of COL1A1, which was similar to the effect of colon cancer cells. CONCLUSION This study identified key fibroblast subclusters with prognostic value and implied that lactylation might help transform fibroblasts into CAFs in colon cancer for the first time, which provides new paths for understanding the evolution of CAFs and cancer therapeutic strategies.
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Affiliation(s)
- Lunxi Liang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Changsha, China
| | - Xueer Yang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Changsha, China
| | - Shuoyi Yao
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Changsha, China
| | - Xinmeng Li
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Changsha, China
| | - Fen Wang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Changsha, China.
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Li C, Zhao Y, Li Q, Chen R, Feng Y, Sang X, Li X, Shen B, Jiang N, Chen Q. The TgAMPK-TgPFKII axis essentially regulates protein lactylation in the zoonotic parasite Toxoplasma gondii. Microbiol Spectr 2025; 13:e0204424. [PMID: 39918324 PMCID: PMC11878075 DOI: 10.1128/spectrum.02044-24] [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: 08/13/2024] [Accepted: 01/23/2025] [Indexed: 03/05/2025] Open
Abstract
Toxoplasma gondii infects nucleated cells of warm-blooded animals and cause zoonotic toxoplasmosis. Lysine lactylation, as a novel post-translational modification, is essential for epigenetic regulation and cellular processes, and proteomic analyses have shown that lactylated proteins are involved in a wide range of biological processes including energy metabolism, gene regulation, and protein biosynthesis. Additionally, protein lactylation is prevalent in T. gondii, while its regulatory mechanisms have not been fully understood. In this study, we investigated the role of T. gondii phosphofructokinase-2 (TgPFKII) and the adenosine-5'-monophosphate-activated protein kinase (AMPK) signaling pathway in the invasion, replication, and lactylation regulation of T. gondii. We localized TgPFKII in the cytoplasm of T. gondii tachyzoites and demonstrated its necessity for parasite growth and protein lactylation through auxin-induced degradation. Our results showed that inhibition of the AMPK pathway led to decreased TgPFKII expression and reduced protein lactylation levels. Furthermore, AMPK-specific inhibitors significantly impaired parasite invasion and proliferation. These findings highlight TgPFKII as a crucial regulator of lactylation and underscore the importance of the AMPK pathway in T. gondii's pathogenic mechanisms, offering potential targets for therapeutic intervention.IMPORTANCEUnderstanding the intricate mechanisms by which Toxoplasma gondii invades and proliferates within host cells is essential for developing novel therapeutic strategies against toxoplasmosis. This study focuses on the pivotal roles of T. gondii phosphofructokinase-2 (TgPFKII) and the adenosine-5'-monophosphate-activated protein kinase (AMPK) signaling pathway in regulating protein lactylation in association with parasite invasion and growth. By elucidating the cellular localization and functional importance of TgPFKII, as well as its regulation through AMPK-specific inhibitors, we provide comprehensive insights into the metabolic and signaling networks that underpin T. gondii pathogenicity. Our findings reveal that TgPFKII is a critical regulator of lactylation and that the AMPK pathway significantly influences T. gondii's ability to invade and replicate within host cells. These insights pave the way for targeted interventions aimed at disrupting key metabolic and signaling pathways in T. gondii, potentially leading to more effective treatments for toxoplasmosis.
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Affiliation(s)
- Chenghuan Li
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, China
| | - Yang Zhao
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, China
| | - Qilong Li
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, China
| | - Ran Chen
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, China
| | - Ying Feng
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, China
| | - Xiaoyu Sang
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, China
| | - Xiangrui Li
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Bang Shen
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Ning Jiang
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, China
| | - Qijun Chen
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, China
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Li S, Dong L, Wang K. Current and future perspectives of lysine lactylation in cancer. Trends Cell Biol 2025; 35:190-193. [PMID: 39837737 DOI: 10.1016/j.tcb.2024.12.015] [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: 10/04/2024] [Revised: 12/28/2024] [Accepted: 12/30/2024] [Indexed: 01/23/2025]
Abstract
Lactate, a glycolytic intermediate, has a crucial role in cancer metabolism and microenvironment remodeling. Recently, researchers found that lactate mediates lysine lactylation, a novel protein post-translational modification (PTM). Here, we summarize the mechanism and role of lysine lactylation in cancer, and discuss the potential of targeting lysine lactylation in cancer therapy.
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Affiliation(s)
- Sijia Li
- West China School of Basic Medical Sciences and Forensic Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Lixia Dong
- West China School of Basic Medical Sciences and Forensic Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Kui Wang
- West China School of Basic Medical Sciences and Forensic Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
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47
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Rho H, Hay N. Protein lactylation in cancer: mechanisms and potential therapeutic implications. Exp Mol Med 2025; 57:545-553. [PMID: 40128358 PMCID: PMC11958728 DOI: 10.1038/s12276-025-01410-7] [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: 08/01/2024] [Revised: 11/14/2024] [Accepted: 12/06/2024] [Indexed: 03/26/2025] Open
Abstract
Increased glycolysis, which leads to high lactate production, is a common feature of cancer cells. Recent evidence suggests that lactate plays a role in the post-translational modification of histone and nonhistone proteins via lactylation. In contrast to genetic mutations, lactylation in cancer cells is reversible. Thus, reversing lactylation can be exploited as a pharmacological intervention for various cancers. Here we discuss recent advances in histone and nonhistone lactylation in cancer, including L-, D- and S-lactylation, as well as alanyl-tRNA synthetase as a novel lactyltransferase. We also discuss potential approaches for targeting lactylation as a therapeutic opportunity in cancer treatment.
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Affiliation(s)
- Hyunsoo Rho
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
| | - Nissim Hay
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
- Research and Development Section, Jesse Brown VA Medical Center, Chicago, IL, USA.
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48
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Wang Y, Ge Y, Hua S, Shen C, Cai B, Zhao H. Aloe-Emodin Improves Mitophagy in Alzheimer's Disease via Activating the AMPK/PGC-1α/SIRT3 Signaling Pathway. CNS Neurosci Ther 2025; 31:e70346. [PMID: 40125832 PMCID: PMC11931456 DOI: 10.1111/cns.70346] [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: 12/19/2024] [Revised: 02/22/2025] [Accepted: 03/11/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Impaired mitophagy results in the accumulation of defective mitochondria that are unable to be cleared effectively in Alzheimer's disease (AD). Aloe-emodin (AE), a key component of the traditional Chinese medicine Rhubarb, exhibits neuroprotective effects against Alzheimer's disease, though the underlying mechanism remains unclear. Studying aloe-emodin's role in enhancing mitophagy is vital for improving cognitive function and reducing neuronal damage in Alzheimer's disease. METHODS The APP/PS1 double transgenic mice were adopted as models for AD to assess the effects of aloe-emodin upon cognitive function and its neuroprotective impact on hippocampal neurons. Additionally, we investigated the regulatory mechanisms of proteins within the aforementioned pathway, and the morphological characteristics of mitophagy-related proteins. An AD hippocampal neuron model was developed using Aβ25-35 to evaluate the mitochondrial function, the protein expression of such a pathway and the mitophagy. This approach aims to elucidate the effects and underlying mechanisms of aloe-emodin in relation to AD. RESULTS AE activates mitophagy in neurons, improves cognitive dysfunction, reduces hippocampal damage, and alleviates AD symptoms in model mice. AE activates the expression of AMPK, PGC-1α and SIRT3. Increased expression of SIRT3 in mitochondria promotes mitophagy and regulates the function of mitochondrial proteins. When mitochondrial autophagy is enhanced, the expression of Beclin1, LC3, P62, Parkin, and PINK1-related proteins changes. Further in vitro experiments showed that AE can enhance mitochondrial function in Alzheimer's disease cell models. The mitochondrial membrane potential, GSH, ROS and Ca2+ levels gradually recover, alleviating the pathological manifestations of AD. Knocking down SIRT3 leads to increased mitochondrial damage and a reduction in mitophagy in HT22 cells. CONCLUSION Experimental results show that AE can activate mitophagy through AMPK/PGC-1α/SIRT3 pathway, alleviate cognitive dysfunction in AD, and reduce damage to hippocampal neurons.
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Affiliation(s)
- Yulu Wang
- College of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
| | - Yunzhi Ge
- College of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
| | - Siyu Hua
- College of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
| | - Chenrui Shen
- College of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
| | - Biao Cai
- College of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
- Institute of Integrated Chinese and Western MedicineAnhui Academy of Chinese MedicineHefeiChina
- Key Laboratory of Xin'an MedicineAnhui University of Chinese Medicine, Ministry of EducationHefeiChina
- Anhui Province Key Laboratory of Chinese Medicinal FormulaHefeiChina
| | - Han Zhao
- College of Integrated Chinese and Western MedicineAnhui University of Chinese MedicineHefeiChina
- Institute of Integrated Chinese and Western MedicineAnhui Academy of Chinese MedicineHefeiChina
- Key Laboratory of Xin'an MedicineAnhui University of Chinese Medicine, Ministry of EducationHefeiChina
- Anhui Province Key Laboratory of Chinese Medicinal FormulaHefeiChina
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Luo Y, Zhang N, Ye J, Wang Z, Zhou X, Liu J, Cai J, Li C, Chen L. Unveiling lactylation modification: A new hope for cancer treatment. Biomed Pharmacother 2025; 184:117934. [PMID: 39986235 DOI: 10.1016/j.biopha.2025.117934] [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: 12/29/2024] [Revised: 02/13/2025] [Accepted: 02/18/2025] [Indexed: 02/24/2025] Open
Abstract
This review article delves into the multifaceted role of lactylation modification in antitumor therapy, revealing the complex interplay between lactylation modification and the tumor microenvironment (TME), metabolic reprogramming, gene expression, and immunotherapy. As an emerging epigenetic modification, lactylation has a significant impact on the metabolic pathways of tumor cells, immune evasion, gene expression regulation, and sensitivity to chemotherapy drugs. Studies have shown that lactylation modification significantly alters the development and therapeutic response of tumors by affecting metabolites in the TME, immune cell functions, and signaling pathways. In the field of immunotherapy, the regulatory role of lactylation modification provides a new perspective and potential targets for tumor treatment, including modulating the sensitivity of tumors to immunotherapy by affecting the expression of immune checkpoint molecules and the infiltration of immune cells. Moreover, research progress on lactylation modification in various types of tumors indicates that it may serve as a biomarker to predict patients' responses to chemotherapy and immunotherapy. Overall, research on lactylation modification provides a theoretical foundation for the development of new tumor treatment strategies and holds promise for improving patient prognosis and quality of life. Future research will further explore the application potential of lactylation modification in tumor therapy and how to improve treatment efficacy by targeting lactylation modification.
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Affiliation(s)
- Yuxiang Luo
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Ning Zhang
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jiarong Ye
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Zuao Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Xinchi Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jipeng Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Jing Cai
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
| | - Chen Li
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China; Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease, Jiangxi 330006, China; Institute of Minimally Invasive Orthopedics, Nanchang University, Jiangxi 330006, China.
| | - Leifeng Chen
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Precision Oncology Medicine Center,The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People's Republic of China.
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50
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Zhang M, Kong X, Wu C, Li J, Yang H, Huang L. The role of lactate and lactylation in ischemic cardiomyopathy: Mechanisms and gene expression. Exp Mol Pathol 2025; 141:104957. [PMID: 40020527 DOI: 10.1016/j.yexmp.2025.104957] [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: 05/30/2024] [Revised: 02/07/2025] [Accepted: 02/12/2025] [Indexed: 03/03/2025]
Abstract
Ischemic cardiomyopathy (ICM) is a significant global public health issue, with its pathophysiology encompassing atherosclerotic plaque formation, thrombosis, hypoperfusion, ischemic cell death, and left ventricular remodeling. Lactate is not only regarded as an energy metabolite but also acts as a signaling molecule that influences various physiological processes, regulating metabolism and muscle contraction. Lactylation, an emerging epigenetic modification, affects protein functionality and gene expression through the P300 enzyme. In ICM, lactate accumulation leads to pH imbalance and myocardial cell dysfunction, impacting cellular signaling. This paper will analyze the role of lactylation in ICM, focusing on coronary artery disease (ASCVD) and myocardial infarction (MI). It will also explore the differential expression and immunological characteristics of lactylation-related genes in normal and ICM tissues, providing potential targets for future research.
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Affiliation(s)
- Mei Zhang
- Department of Clinical Nursing, The Second Xiangya Hospital of Central South University, Changsha, China; Xiangya School of Nursing, Central South University, Changsha, China
| | - Xue Kong
- Department of Clinical Nursing, The Second Xiangya Hospital of Central South University, Changsha, China; Xiangya School of Nursing, Central South University, Changsha, China
| | - Chenlu Wu
- Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China
| | - Jiuhong Li
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hui Yang
- Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China.
| | - Lingzhi Huang
- Department of Clinical Nursing, The Second Xiangya Hospital of Central South University, Changsha, China; Xiangya School of Nursing, Central South University, Changsha, China.
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