Pub Date : 2025-12-17DOI: 10.1016/j.metabol.2025.156469
Dong-Ho Kim , Mi Kyung Kim , Daehoon Kim , Eun-Jun Kwon , Jieun Shin , Sebin Lee , Bae-Gon Kang , Jae Won Yun , Jaebon Lee , Hye Won Lee , Byoung Kuk Jang , Ghilsuk Yoon , Kwang-Hyeon Liu , Jun-Kyu Byun , Yeon-Kyung Choi , Keun-Gyu Park
<div><h3>Background</h3><div>Immune checkpoint blockade (ICB) has revolutionized treatment of hepatocellular carcinoma (HCC), but its efficacy remains limited. Recent studies demonstrate that resistance to ferroptosis is a significant barrier to the success of ICB.</div></div><div><h3>Methods</h3><div>Ferroptosis was assessed by measuring C11-BODIPY fluorescence and 4-hydroxynonenal (4-HNE) staining. Epigenetic regulation of hepcidin under fatty acid-rich conditions in HCC cells was investigated through chromatin immunoprecipitation and histone methylation analyses. Clinical relevance was evaluated using ICB response datasets and analyses of tumor tissues from HCC patients.</div></div><div><h3>Results</h3><div>We demonstrate that prolonged exposure to high palmitate concentrations induces ferroptosis resistance in HCC cells by altering glutamine availability. Mechanistically, chronic exposure to palmitate and high-fat diet-feeding reduced glutamine-derived α-KG concentrations in HCC cells, leading to a H3K27me3-mediated reduction in <strong>hepcidin</strong> and depletion of the intracellular labile iron pool, thereby promoting resistance to anti-programmed death-ligand 1 (anti-PD-L1)-induced ferroptosis. This resistance was reversed by the EZH2 inhibitor tazemetostat, which epigenetically restored hepcidin expression in both <em>in vitro</em> and <em>in vivo</em> models. Notably, tumor tissues from HCC patients exhibited high FFA levels, along with low levels of glutamine, <strong>hepcidin,</strong> and iron, which correlated with shorter overall survival. H3K27me3-mediated suppression of hepcidin was further confirmed in patient cohorts.</div></div><div><h3>Conclusion</h3><div>Our study uncovers a previously unrecognized type of palmitate-induced metabolic reprogramming that confers resistance to ICB-induced ferroptosis on HCC, and propose a therapeutic strategy to overcome ferroptosis resistance under free fatty acid-rich conditions.</div></div><div><h3>Abbreviations</h3><div><span><div><div><table><tbody><tr><td>ICB</td><td>Immune checkpoint blockade</td></tr><tr><td>xCT</td><td>cystine/glutamate antiporter</td></tr><tr><td>CoQ10</td><td>coenzyme Q10</td></tr><tr><td>FSP1</td><td>ferroptosis suppressor protein 1</td></tr><tr><td>NADPH</td><td>nicotinamide adenine dinucleotide phosphate, reduced form</td></tr><tr><td>GSH</td><td>glutathione</td></tr><tr><td>GSSG</td><td>glutathione disulfide</td></tr><tr><td>HCC</td><td>hepatocellular carcinoma</td></tr><tr><td>AD</td><td>palmitate-adapted HCC cells</td></tr><tr><td>PI</td><td>propidium iodide</td></tr><tr><td>ROS</td><td>lipid reactive oxygen species</td></tr><tr><td>IKE</td><td>imidazole ketone erastin</td></tr><tr><td>GPX4</td><td>glutathione peroxidase-4</td></tr><tr><td>LIP</td><td>labile iron pool</td></tr><tr><td>SLC</td><td>solute carrier</td></tr><tr><td>NRF2</td><td>nuclear factor erythroid 2-related factor 2</td></tr><tr><td>FFA</td><td>free fatty acid</td></tr><tr><td>LFD</td><td>l
{"title":"Liver cancer chronically exposed to palmitate acquires ferroptosis resistance via the downregulation of glutamine-driven hepcidin expression","authors":"Dong-Ho Kim , Mi Kyung Kim , Daehoon Kim , Eun-Jun Kwon , Jieun Shin , Sebin Lee , Bae-Gon Kang , Jae Won Yun , Jaebon Lee , Hye Won Lee , Byoung Kuk Jang , Ghilsuk Yoon , Kwang-Hyeon Liu , Jun-Kyu Byun , Yeon-Kyung Choi , Keun-Gyu Park","doi":"10.1016/j.metabol.2025.156469","DOIUrl":"10.1016/j.metabol.2025.156469","url":null,"abstract":"<div><h3>Background</h3><div>Immune checkpoint blockade (ICB) has revolutionized treatment of hepatocellular carcinoma (HCC), but its efficacy remains limited. Recent studies demonstrate that resistance to ferroptosis is a significant barrier to the success of ICB.</div></div><div><h3>Methods</h3><div>Ferroptosis was assessed by measuring C11-BODIPY fluorescence and 4-hydroxynonenal (4-HNE) staining. Epigenetic regulation of hepcidin under fatty acid-rich conditions in HCC cells was investigated through chromatin immunoprecipitation and histone methylation analyses. Clinical relevance was evaluated using ICB response datasets and analyses of tumor tissues from HCC patients.</div></div><div><h3>Results</h3><div>We demonstrate that prolonged exposure to high palmitate concentrations induces ferroptosis resistance in HCC cells by altering glutamine availability. Mechanistically, chronic exposure to palmitate and high-fat diet-feeding reduced glutamine-derived α-KG concentrations in HCC cells, leading to a H3K27me3-mediated reduction in <strong>hepcidin</strong> and depletion of the intracellular labile iron pool, thereby promoting resistance to anti-programmed death-ligand 1 (anti-PD-L1)-induced ferroptosis. This resistance was reversed by the EZH2 inhibitor tazemetostat, which epigenetically restored hepcidin expression in both <em>in vitro</em> and <em>in vivo</em> models. Notably, tumor tissues from HCC patients exhibited high FFA levels, along with low levels of glutamine, <strong>hepcidin,</strong> and iron, which correlated with shorter overall survival. H3K27me3-mediated suppression of hepcidin was further confirmed in patient cohorts.</div></div><div><h3>Conclusion</h3><div>Our study uncovers a previously unrecognized type of palmitate-induced metabolic reprogramming that confers resistance to ICB-induced ferroptosis on HCC, and propose a therapeutic strategy to overcome ferroptosis resistance under free fatty acid-rich conditions.</div></div><div><h3>Abbreviations</h3><div><span><div><div><table><tbody><tr><td>ICB</td><td>Immune checkpoint blockade</td></tr><tr><td>xCT</td><td>cystine/glutamate antiporter</td></tr><tr><td>CoQ10</td><td>coenzyme Q10</td></tr><tr><td>FSP1</td><td>ferroptosis suppressor protein 1</td></tr><tr><td>NADPH</td><td>nicotinamide adenine dinucleotide phosphate, reduced form</td></tr><tr><td>GSH</td><td>glutathione</td></tr><tr><td>GSSG</td><td>glutathione disulfide</td></tr><tr><td>HCC</td><td>hepatocellular carcinoma</td></tr><tr><td>AD</td><td>palmitate-adapted HCC cells</td></tr><tr><td>PI</td><td>propidium iodide</td></tr><tr><td>ROS</td><td>lipid reactive oxygen species</td></tr><tr><td>IKE</td><td>imidazole ketone erastin</td></tr><tr><td>GPX4</td><td>glutathione peroxidase-4</td></tr><tr><td>LIP</td><td>labile iron pool</td></tr><tr><td>SLC</td><td>solute carrier</td></tr><tr><td>NRF2</td><td>nuclear factor erythroid 2-related factor 2</td></tr><tr><td>FFA</td><td>free fatty acid</td></tr><tr><td>LFD</td><td>l","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156469"},"PeriodicalIF":11.9,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794302","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}
Pub Date : 2025-12-17DOI: 10.1016/j.metabol.2025.156471
Francesca D'Addio , Loredana Bucciarelli , Maria Elena Lunati , Paolo Fiorina
A growing body of evidence suggests that neurogenerative disorders are increasingly common in individuals with type 1 diabetes (T1D) and should be considered part of the heterogeneous impairment of the nervous system linked to the T1D condition. The already established association between brain health and blood glucose metabolic control pushes to normalize glycemia in individuals with neurodegenerative diseases as well as in those with T1D. Normoglycemia has, indeed, been associated with reduced brain atrophy and preserved neuronal plasticity and function. Interestingly, immune dysregulation recently demonstrated in neurodegenerative diseases may be highly relevant given the autoimmune nature of T1D. Poor glycemic control and a disrupted immune response may act as common pathogenic mechanisms that increase the incidence of neurodegenerative disorders in individuals with T1D and may unveil new diagnostic and therapeutic paths for future clinical advancements. In this narrative review, we summarize new evidence showing that brain damage and cognitive dysfunction are linked to T1D and delineate the role of altered glycemic control, neuronal loss and immune dysregulation. We also discuss novel therapeutic approaches that target the aforementioned mechanisms and may help prevent the onset of neurodegenerative disorders in individuals with T1D.
{"title":"Metabolic and immune dysfunction at the crossroads between type 1 diabetes and neurodegeneration","authors":"Francesca D'Addio , Loredana Bucciarelli , Maria Elena Lunati , Paolo Fiorina","doi":"10.1016/j.metabol.2025.156471","DOIUrl":"10.1016/j.metabol.2025.156471","url":null,"abstract":"<div><div>A growing body of evidence suggests that neurogenerative disorders are increasingly common in individuals with type 1 diabetes (T1D) and should be considered part of the heterogeneous impairment of the nervous system linked to the T1D condition. The already established association between brain health and blood glucose metabolic control pushes to normalize glycemia in individuals with neurodegenerative diseases as well as in those with T1D. Normoglycemia has, indeed, been associated with reduced brain atrophy and preserved neuronal plasticity and function. Interestingly, immune dysregulation recently demonstrated in neurodegenerative diseases may be highly relevant given the autoimmune nature of T1D. Poor glycemic control and a disrupted immune response may act as common pathogenic mechanisms that increase the incidence of neurodegenerative disorders in individuals with T1D and may unveil new diagnostic and therapeutic paths for future clinical advancements. In this narrative review, we summarize new evidence showing that brain damage and cognitive dysfunction are linked to T1D and delineate the role of altered glycemic control, neuronal loss and immune dysregulation. We also discuss novel therapeutic approaches that target the aforementioned mechanisms and may help prevent the onset of neurodegenerative disorders in individuals with T1D.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156471"},"PeriodicalIF":11.9,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794290","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}
Pub Date : 2025-12-10DOI: 10.1016/j.metabol.2025.156466
Guanghong Jia , William P. Fay , Christos S. Mantzoros , Michael A. Hill
{"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}
Pub Date : 2025-12-09DOI: 10.1016/j.metabol.2025.156464
Sibo Wang , Qian Ren , Yansheng Huang , Yibo Ma , Xuefang Zhang , Yuan Liu , Baorong He , Liang Yan
{"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}
Pub Date : 2025-12-08DOI: 10.1016/j.metabol.2025.156467
Guochang You , Kangjie Wang , Runnan Shen , Xiong Chen , Jinjin Jiang , Yunhao Sun , Dan Wu , Jiatang Xu , Kai Huang , Chen Yao
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 (n = 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., SERPINA1, FADS 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.
目前的代谢组学衰老时钟不能充分捕捉生物衰老轨迹中的个体异质性，限制了它们的临床应用。在这里，我们在英国生物银行（n = 196,790）中使用249种血浆代谢物的综合面板开发了代谢组学年龄时钟。该框架被训练用于预测表型年龄（PhenoAge），表型年龄是一种经过验证的复合生物标志物，整合了多个系统的临床化学成分，并评估了其预测心血管疾病（cvd）和痴呆的实用性。我们发现，这种新的测量方法准确地预测了实际的表型年龄（Pearson’s r = 0.90），并与七种心血管疾病的发病率显著相关，包括主要不良心血管事件、动脉粥样硬化性心血管疾病、心肌梗死、中风、主动脉狭窄、心力衰竭和腹主动脉瘤，但与痴呆无关。此外，代谢组学衰老与生物、物理和认知年龄相关的表型有关，包括端粒长度、脆弱指数和反应时间。通过c统计量和净重分类指数测量，将代谢组年龄时钟与预防（CVD事件预测风险）风险评分相结合，适度提高了表现。遗传分析揭示了91个基因组位点和168个基因（如SERPINA1， FADS簇），组织富集分析强调了肝脏在代谢衰老中的重要作用。通过将代谢组学特征与多系统衰老信息联系起来，该框架提供了一种与年龄相关的功能状态和心血管风险相关的生物衰老测量方法。
{"title":"Metabolomic aging clock predicts risk of different cardiovascular diseases in the UK Biobank","authors":"Guochang You , Kangjie Wang , Runnan Shen , Xiong Chen , Jinjin Jiang , Yunhao Sun , Dan Wu , Jiatang Xu , Kai Huang , 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}
Pub Date : 2025-12-04DOI: 10.1016/j.metabol.2025.156460
Min Ye , Shenghui Feng , Zixuan Xu , Wenfeng He , Chen Liu , Wengen Zhu
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.
{"title":"Aging and metabolism in HFpEF: Pathophysiology and therapeutic implications","authors":"Min Ye , Shenghui Feng , Zixuan Xu , Wenfeng He , Chen Liu , 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<sup>+</sup> 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<sup>+</sup> 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}
Pub Date : 2025-12-03DOI: 10.1016/j.metabol.2025.156465
Martin Riecan , Barbora Judita Kasperova , Michaela Vondrackova , Petra Janovska , Eliska Haasova , Katerina Adamcova , Peter Ivak , Daniel Hlavacek , Katerina Kroupova , Tomas Cajka , Jan Kopecky , Soňa Štemberková Hubáčková , Milos Mraz , Ivan Netuka , Vojtech Melenovsky , Martin Haluzik , Ondrej Kuda
Background
Heart failure (HF) progression involves complex metabolic and multi-organ alterations, but the specific adaptations in adipose tissue are not fully understood.
Aims
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.
Methods
Clinical and metabolomic profiling were performed on metabolically stable controls (n = 34), patients with mild HFrEF (n = 45), and severe HFrEF (n = 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.
Results
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.
Conclusions
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.
{"title":"Epicardial adipose tissue produces L-3-hydroxybutyrate in advanced heart failure: direct analysis of fat metabolic remodeling","authors":"Martin Riecan , Barbora Judita Kasperova , Michaela Vondrackova , Petra Janovska , Eliska Haasova , Katerina Adamcova , Peter Ivak , Daniel Hlavacek , Katerina Kroupova , Tomas Cajka , Jan Kopecky , Soňa Štemberková Hubáčková , Milos Mraz , Ivan Netuka , Vojtech Melenovsky , Martin Haluzik , 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}
Pub Date : 2025-12-03DOI: 10.1016/j.metabol.2025.156463
Paschalis Karakasis , Konstantinos Vlachos , Antonios P. Antoniadis , Konstantinos C. Siontis , Dimitrios Patoulias , Nikolaos Fragakis , Christos S. Mantzoros
Background and aims
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.
Methods
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.
Results
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; P = 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.
Conclusions
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.
{"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 , Konstantinos Vlachos , Antonios P. Antoniadis , Konstantinos C. Siontis , Dimitrios Patoulias , Nikolaos Fragakis , 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; I<sup>2</sup> = 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}
Pub Date : 2025-12-01DOI: 10.1016/j.metabol.2025.156462
Yang Zhou , Yuhang Dai , Mengyao Qin , Yecheng Li , Lunan Shi , Hao Chen , Hui Fan , Yunli Yu , Le Guo , Jing Xiong
Background & aims
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.
Methods
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.
Results
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.
Conclusions
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.
{"title":"FAM83A acts as an amplifier for lipogenic signaling to facilitate the pathogenesis of metabolic dysfunction-associated steatohepatitis","authors":"Yang Zhou , Yuhang Dai , Mengyao Qin , Yecheng Li , Lunan Shi , Hao Chen , Hui Fan , Yunli Yu , Le Guo , Jing Xiong","doi":"10.1016/j.metabol.2025.156462","DOIUrl":"10.1016/j.metabol.2025.156462","url":null,"abstract":"<div><h3>Background & 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}
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