Metabolism: clinical and experimental最新文献

{"title":"ALDH2 variants – a role in cardiometabolic syndrome","authors":"Guanghong Jia , William P. Fay , Christos S. Mantzoros , Michael A. Hill","doi":"10.1016/j.metabol.2025.156466","DOIUrl":"10.1016/j.metabol.2025.156466","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156466"},"PeriodicalIF":11.9,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Emerging roles of arginine metabolism in skeletal health and disease” [Metabolism 2025 Nov 19:175:156451. / PMID: 41270967]","authors":"Sibo Wang , Qian Ren , Yansheng Huang , Yibo Ma , Xuefang Zhang , Yuan Liu , Baorong He , Liang Yan","doi":"10.1016/j.metabol.2025.156464","DOIUrl":"10.1016/j.metabol.2025.156464","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156464"},"PeriodicalIF":11.9,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomic aging clock predicts risk of different cardiovascular diseases in the UK Biobank","authors":"Guochang You ,&nbsp;Kangjie Wang ,&nbsp;Runnan Shen ,&nbsp;Xiong Chen ,&nbsp;Jinjin Jiang ,&nbsp;Yunhao Sun ,&nbsp;Dan Wu ,&nbsp;Jiatang Xu ,&nbsp;Kai Huang ,&nbsp;Chen Yao","doi":"10.1016/j.metabol.2025.156467","DOIUrl":"10.1016/j.metabol.2025.156467","url":null,"abstract":"<div><div>Current metabolomic aging clocks inadequately capture individual heterogeneity in biological aging trajectories, constraining their clinical utility. Here, we developed a metabolomic age clock in the UK Biobank (<em>n</em> = 196,790) using a comprehensive panel of 249 plasma metabolites. This framework was trained to predict phenotypic age (PhenoAge), a validated composite biomarker that integrates clinical chemistry across multiple systems, and was evaluated for its utility to predict incident cardiovascular diseases (CVDs) and dementia. We found that this new measure accurately predicted actual PhenoAge (Pearson's r = 0.90) and was significantly associated with the incidence of seven CVDs, including major adverse cardiovascular events, atherosclerotic cardiovascular disease, myocardial infarction, stroke, aortic stenosis, heart failure, and abdominal aortic aneurysm, but not dementia. Furthermore, metabolomic aging was associated with biological, physical, and cognitive age-related phenotypes, comprising telomere length, frailty index, and reaction time. Incorporating the metabolomic age clock with PREVENT (Predicting Risk of CVD Events) risk score modestly improved the performance, as measured by C-statistic and net reclassification index. Genetic analyses revealed 91 genomic loci and 168 genes (e.g., <em>SERPINA1</em>, <em>FADS</em> cluster), with tissue-enrichment analysis highlighting the liver's significant role in metabolic aging. By bridging metabolomic profiles with multisystem aging information, this framework provides a measure of biological aging that is associated with age-related functional status and cardiovascular risk.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156467"},"PeriodicalIF":11.9,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging and metabolism in HFpEF: Pathophysiology and therapeutic implications","authors":"Min Ye ,&nbsp;Shenghui Feng ,&nbsp;Zixuan Xu ,&nbsp;Wenfeng He ,&nbsp;Chen Liu ,&nbsp;Wengen Zhu","doi":"10.1016/j.metabol.2025.156460","DOIUrl":"10.1016/j.metabol.2025.156460","url":null,"abstract":"<div><div>Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as an age-predominant syndrome characterized by diastolic dysfunction despite preserved systolic performance. In the aged myocardium, fatty acid oxidation capacity declines, while glycolytic flux increases; however, impaired pyruvate oxidation limits mitochondrial glucose oxidation, resulting in suboptimal ATP yield per oxygen molecule and worsening energetic inefficiency. Mitochondrial deficits, marked by reduced biogenesis, NAD⁺ depletion related to reduced sirtuin activity and consequent hyperacetylation of oxidative enzymes, and impaired electron-transport capacity, further diminish bioenergetic reserve and elevate reactive oxygen species generation. Concurrently, inflammaging and proteostatic collapse promote chronic low-grade inflammation, misfolded protein accumulation, and myocardial fibrosis, collectively contributing to increased ventricular stiffness and progressive HFpEF development. Therapeutic strategies targeting these interconnected pathways show considerable promise. Preclinical studies suggest that interventions such as NAD⁺ precursor supplementation, mTORC1 inhibition, and β-hydroxybutyrate administration can ameliorate HFpEF-like phenotypes by improving mitochondrial efficiency and reducing inflammation. SGLT2 inhibitors and GLP-1 receptor agonists confer clinically proven benefits in HFpEF, likely via systemic metabolic reprogramming toward more oxygen-efficient substrates and attenuation of inflammation. This review underscores the critical role of aging-associated metabolic and mitochondrial derangements in HFpEF pathogenesis and highlights mechanistically tailored interventions as the next frontier in managing this challenging, age-related syndrome.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156460"},"PeriodicalIF":11.9,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epicardial adipose tissue produces L-3-hydroxybutyrate in advanced heart failure: direct analysis of fat metabolic remodeling","authors":"Martin Riecan ,&nbsp;Barbora Judita Kasperova ,&nbsp;Michaela Vondrackova ,&nbsp;Petra Janovska ,&nbsp;Eliska Haasova ,&nbsp;Katerina Adamcova ,&nbsp;Peter Ivak ,&nbsp;Daniel Hlavacek ,&nbsp;Katerina Kroupova ,&nbsp;Tomas Cajka ,&nbsp;Jan Kopecky ,&nbsp;Soňa Štemberková Hubáčková ,&nbsp;Milos Mraz ,&nbsp;Ivan Netuka ,&nbsp;Vojtech Melenovsky ,&nbsp;Martin Haluzik ,&nbsp;Ondrej Kuda","doi":"10.1016/j.metabol.2025.156465","DOIUrl":"10.1016/j.metabol.2025.156465","url":null,"abstract":"<div><h3>Background</h3><div>Heart failure (HF) progression involves complex metabolic and multi-organ alterations, but the specific adaptations in adipose tissue are not fully understood.</div></div><div><h3>Aims</h3><div>We aimed to characterize the metabolic remodeling of epicardial (EAT) and subcutaneous (SAT) adipose tissues in HF with reduced ejection fraction (HFrEF), focusing on lipid metabolism, fatty acid oxidation, and ketogenesis.</div></div><div><h3>Methods</h3><div>Clinical and metabolomic profiling were performed on metabolically stable controls (<em>n</em> = 34), patients with mild HFrEF (<em>n</em> = 45), and severe HFrEF (<em>n</em> = 129). Metabolomics profiling identified over 800 metabolites in EAT and SAT. Clustering and pathway enrichment analyses defined depot-specific metabolic shifts across HF stages, while gene expression analyses provided mechanistic support.</div></div><div><h3>Results</h3><div>Advancing HF was associated with declining cardiac function, systemic congestion, and a metabolic shift toward catabolism. Metabolomics revealed depot-specific adaptations: SAT transitioned smoothly to enhanced lipolysis, whereas EAT demonstrated impaired triacylglycerol replenishment and disrupted final turn of β-oxidation spiral. Both depots increased reliance on acylcarnitine degradation and lipolysis; however, EAT was uniquely characterized by late-stage impairment in mitochondrial and peroxisomal fatty acid oxidation, leading to elevation of 3-hydroxybutyrate and hydroxybutyrylcarnitine tissue levels. Ex vivo analyses of EAT explants showed significantly increased fraction of L-3-hydroxybutyrate enantiomer, produced by EAT, compared to D-3-hydroxybutyrate enantiomer originating from the liver.</div></div><div><h3>Conclusions</h3><div>HF progression drives major, depot-specific metabolic remodeling in adipose tissue. In advanced HF, EAT shows impaired fatty acid oxidation and enhanced local production of L-3-hydroxybutyrate in the vicinity of myocardium, highlighting the close metabolic cooperation in nutrient supply between EAT and the heart muscle through the coronary circulation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156465"},"PeriodicalIF":11.9,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of GLP-1 receptor agonists and co-agonists on atrial fibrillation risk in overweight or obesity: systematic review and meta-analysis of randomized controlled trials","authors":"Paschalis Karakasis ,&nbsp;Konstantinos Vlachos ,&nbsp;Antonios P. Antoniadis ,&nbsp;Konstantinos C. Siontis ,&nbsp;Dimitrios Patoulias ,&nbsp;Nikolaos Fragakis ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2025.156463","DOIUrl":"10.1016/j.metabol.2025.156463","url":null,"abstract":"<div><h3>Background and aims</h3><div>Overweight and obesity represent major modifiable determinants of atrial fibrillation (AF) incidence and arrhythmia outcomes after AF ablation therapy. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and their next-generation co-agonists exert potent weight-lowering and cardiometabolic effects and may therefore confer antiarrhythmic effects. This meta-analysis aimed to quantitatively assess the effect of GLP-1–based therapies on the risk of AF among individuals with overweight or obesity.</div></div><div><h3>Methods</h3><div>A systematic search of Medline, Scopus, and the Cochrane Library was conducted for randomized controlled trials (RCTs) through October 29, 2025. Data were analyzed using random-effects pairwise meta-analysis.</div></div><div><h3>Results</h3><div>Twenty-four RCTs encompassing 40,694 participants were included. Compared with placebo, treatment with GLP-1RAs or co-agonists resulted in a 18 % relative reduction in AF risk (Risk Ratio = 0.82; 95 % confidence interval, 0.70–0.96; <em>P</em> = 0.012; I² = 0 %). No significant between-subgroup differences were observed according to agent type (single-, dual-, or triple-receptor agonists), individual compound, baseline BMI category (overweight/obesity vs. obesity alone), diabetes inclusion criteria, trial design [cardiovascular outcomes trial (CVOT) vs. non-CVOT], or administration route (oral vs. subcutaneous). Meta-regression analyses identified no significant effect modification by the magnitude of weight reduction or concomitant SGLT2 inhibitor use.</div></div><div><h3>Conclusions</h3><div>Among individuals with overweight or obesity, GLP-1RAs and co-agonists were associated with a lower risk of incident AF event. This cardioprotective benefit may, at least in part, operate independently of the magnitude of weight loss.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156463"},"PeriodicalIF":11.9,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAM83A acts as an amplifier for lipogenic signaling to facilitate the pathogenesis of metabolic dysfunction-associated steatohepatitis","authors":"Yang Zhou ,&nbsp;Yuhang Dai ,&nbsp;Mengyao Qin ,&nbsp;Yecheng Li ,&nbsp;Lunan Shi ,&nbsp;Hao Chen ,&nbsp;Hui Fan ,&nbsp;Yunli Yu ,&nbsp;Le Guo ,&nbsp;Jing Xiong","doi":"10.1016/j.metabol.2025.156462","DOIUrl":"10.1016/j.metabol.2025.156462","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Metabolic dysfunction-associated fatty liver disease (MAFLD) and its more severe manifestation, metabolic-associated steatohepatitis (MASH), are intimately linked to disturbances in lipid metabolism. Although downstream signaling pathways of epidermal growth factor receptor (EGFR), including extracellular signal-regulated kinase (ERK) and proto-oncogene serine/threonine kinase (RAF1), exhibited heightened activation during MASH progression, their specific roles and underlying mechanisms in driving MASH pathogenesis remain inadequately elucidated.</div></div><div><h3>Methods</h3><div>A comprehensive transcriptomic analysis was performed to indentify key genes involved in MAFLD development. Murine models with hepatocyte-specific depletion or overexpression of FAM83A were subjected to either a high-fat diet (HFD) for 8 or 14 weeks to simulate simple steatosis (MAFL) and MASH, respectively, or a choline-deficient high-fat diet (CDAHFD) to accelerate MASH progression.</div></div><div><h3>Results</h3><div>FAM83A, recognized as a downstream effector of EGFR that activates the ERK signaling pathway, was predominantly expressed in hepatoctyes and upregulated during MASH pathogenesis in both animal models and clinical patients. Hepatocyte-specific FAM83A knockout delayed MASH progression and mitigated hepatic inflammation and fibrosis. Conversely, overexpression of FAM83A exacerbated MASH pathology, evidence by increased lipid accumulation, inflammation and fibrosis. Mechanistically, insulin induces transcriptional expression of FAM83A, which physically bound to RAF1, enhancing its phosphorylation and subsequent ERK signaling activation. Furthermore, FAM83A-mediated upregulatation of lipogenic gene expression and lipogenesis was significantly inhibited by the treatment of RAF1 inhibitor sorafenib or ERK inhibitor PD98059.</div></div><div><h3>Conclusions</h3><div>FAM83A promotes MASH pathogenesis by interacting with RAF1 to activate ERK signaling, thereby stimulating fatty acid and cholesterol biosynthesis. Targeting this axis may offer therapeutic potential for MASH and metabolic dyslipidemia.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156462"},"PeriodicalIF":11.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling the obesity paradox in cancer: An umbrella review of protective associations and evidence credibility across 13 malignancies","authors":"Lulin Yu ,&nbsp;Jing Yuan ,&nbsp;Mingxian Meng ,&nbsp;Hejing Pan ,&nbsp;Long Ge ,&nbsp;Liaoyao Wang ,&nbsp;Xuanlin Li","doi":"10.1016/j.metabol.2025.156461","DOIUrl":"10.1016/j.metabol.2025.156461","url":null,"abstract":"<div><h3>Background</h3><div>The “obesity paradox” in cancer remains controversial amid inconsistent meta-analyses. This umbrella review re-analyses evidence across 13 malignancies using pre-specified credibility criteria to clarify associations.</div></div><div><h3>Methods</h3><div>We conducted an umbrella review of systematic reviews and meta-analyses investigating obesity and cancer incidence or prognosis. PubMed, Embase, and Cochrane Library were searched from inception to August 2025. Evidence credibility was graded using the following criteria: statistical significance, heterogeneity, 95 % prediction intervals, small-study effects, excess significance bias, and methodological quality assessment.</div></div><div><h3>Findings</h3><div>Based on 33 included articles (comprising 145 associations across 13 cancer types), only two associations met the convincing evidence criteria: higher BMI was associated with a reduced incidence of oral cancer (relative risk [RR] = 0.93, 95 % CI: 0.91–0.96), and excess weight was associated with a reduced incidence of lung cancer in the Chinese population (odds ratio [OR] = 0.68, 95 % CI: 0.59–0.79). Highly suggestive evidence has revealed associations in lung cancer (reduced incidence, fewer surgical complications and prolonged cancer-specific survival), breast cancer (reduced incidence and decreased likelihood of lymph node metastasis), renal cell carcinoma (prolonged overall survival) and prostate cancer (prolonged overall survival). Of the remaining associations, 20 were suggestive, 51 weak, and 53 non-significant.</div></div><div><h3>Conclusions</h3><div>Only 21 (14 %) meta-analyses provided convincing or highly suggestive evidence, demonstrating potential associations of obesity in specific oncological contexts pertaining to both reduced incidence risk and improved prognostic outcomes. This synthesis also highlights critical gaps in current evidence, emphasising the need for standardised adiposity metrics, more prudent stratification, and rigorous methodology.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156461"},"PeriodicalIF":11.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meteorin-like protein inhibits vascular smooth muscle cell-derived foam cell formation and atherosclerosis via KIT- endoplasmic reticulum stress signaling","authors":"Xu Chen ,&nbsp;Xueying Jiang ,&nbsp;Siyu Hou ,&nbsp;Fengling Lai ,&nbsp;Keqing Hu ,&nbsp;Jie Li ,&nbsp;Ting Yang ,&nbsp;Xinxin Shen ,&nbsp;Huimin Chen ,&nbsp;Shen Chen ,&nbsp;Xianfei Guo ,&nbsp;Yan Zheng ,&nbsp;Tao Xu ,&nbsp;Guohai Su ,&nbsp;Rong Huang","doi":"10.1016/j.metabol.2025.156459","DOIUrl":"10.1016/j.metabol.2025.156459","url":null,"abstract":"<div><h3>Objective</h3><div>Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known metabolic and anti-inflammatory effects, has been linked to cardiovascular protection, but its role in atherosclerosis is not well defined. This study investigated the function of METRNL in VSMC-derived foam cell formation and atherosclerosis and explored the underlying signaling mechanisms.</div></div><div><h3>Methods</h3><div>ApoE^−/− mice were used to investigate the role of METRNL in atherosclerosis. VSMC-derived foam cell formation was evaluated in human VSMC treated with oxidized LDL with or without METRNL supplementation.</div></div><div><h3>Results</h3><div>METRNL levels declined during atherosclerosis progression and were restored during regression. METRNL selectively inhibited foam cell formation in VSMCs—but not in macrophages—by downregulating CD36-mediated cholesterol uptake and suppressing endoplasmic reticulum stress through KIT signaling. Deletion of KIT specifically in smooth muscle cells abolished these protective effects. The transcription factor SP1 was found to bind directly to the METRNL promoter and enhance its expression. Clinically, lower serum METRNL levels were independently associated with increased risk and severity of acute coronary syndrome.</div></div><div><h3>Conclusion</h3><div>METRNL protects against VSMC foam cell formation and atherosclerosis by enhancing KIT signaling, thereby reducing ER stress and subsequent cholesterol uptake. These findings position METRNL as a potential therapeutic target and biomarker for atherosclerotic cardiovascular disease.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156459"},"PeriodicalIF":11.9,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular code of ferroptosis: emerging multi-dimensional modifications and therapeutic targets in hepatic disorders","authors":"Xiaotong Cai ,&nbsp;Yinhao Zhang ,&nbsp;Wenqing Qin ,&nbsp;Xiaojiaoyang Li","doi":"10.1016/j.metabol.2025.156457","DOIUrl":"10.1016/j.metabol.2025.156457","url":null,"abstract":"<div><div>Ferroptosis, a distinct form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a pivotal regulator in the pathogenesis of liver diseases. It functions both as a driver of hepatocyte injury in chronic liver disorders and as a therapeutic vulnerability in hepatocellular carcinoma. This review provides a comprehensive analysis of the regulatory networks of ferroptosis, shaped by both epigenetic and post-translational modifications. Specifically, we detailed how RNA and DNA methylation, non-coding RNAs, histone acetylation and post-translational modifications dynamically modulated the expression, stability and activity of ferroptosis-related molecules, especially for glutathione peroxidase 4, solute carrier family 7 member 11, acyl-CoA synthetase long-chain family member 4 and transferrin receptor 1. By dissecting these multilayered regulatory mechanisms, we delineated how distinct modifications operated, either promoting or suppressing ferroptosis across various liver diseases. Furthermore, we summarized recent advances in therapeutic interventions targeting ferroptosis-related pathways, including their pharmacological mechanisms, efficacy in preclinical models and limitations in clinical translation. Special emphasis was also placed on the complexity of modifications, disease-stage specificity and the topology of modification sites in shaping ferroptosis sensitivity. Collectively, this review highlights ferroptosis as a dynamic and therapeutically actionable within liver pathology and underscores the potential of targeting regulatory modifications to refine strategies for disease intervention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156457"},"PeriodicalIF":11.9,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}