Pub Date : 2026-03-24DOI: 10.1016/j.cmet.2026.03.009
Claire H. Feetham, Sam Groom, Linu M. John, Berit Ostergaard Christoffersen, Valeria Collabolletta, David Lyons, Antony Adamson, Sofia Lundh, Marina Kjærgaard Gerstenberg, Mads Tang-Christensen, Kilian W. Conde-Frieboes, Anna Secher, Ann Maria Kruse Hansen, Simon M. Luckman
{"title":"Analog of prolactin-releasing peptide reduces body weight primarily through sustained fatty acid oxidation rather than hypophagia","authors":"Claire H. Feetham, Sam Groom, Linu M. John, Berit Ostergaard Christoffersen, Valeria Collabolletta, David Lyons, Antony Adamson, Sofia Lundh, Marina Kjærgaard Gerstenberg, Mads Tang-Christensen, Kilian W. Conde-Frieboes, Anna Secher, Ann Maria Kruse Hansen, Simon M. Luckman","doi":"10.1016/j.cmet.2026.03.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.03.009","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"2 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147501746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-23DOI: 10.1016/j.cmet.2026.02.018
Herbert Tilg, Timon E. Adolph, Stefano Romeo, Rohit Loomba
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, affecting one-third of the global population. Most patients exhibit simple steatosis, whereas up to 20% develop metabolic dysfunction-associated steatohepatitis (MASH), potentially culminating in liver cirrhosis and hepatocellular carcinoma. Diverse parallel mechanisms contribute to the development of MASH, which are fueled by hepatic lipotoxicity, intestinal dysbiosis, and pro-inflammatory diets shaping innate and adaptive immune responses. Moreover, adipose tissue is driving systemic inflammation in obesity, contributing to the inflammatory burden in obesity-related MASH. Polygenetic and multiomic risk scores identify distinct types of MASLD with dominant aggressive liver disease or extrahepatic cardiometabolic disease. Here, we review the complexity of multiple parallel inflammatory hits in MASH and delineate that most current MASH drugs exert pleiotropic metabolic and anti-inflammatory properties. These new therapies will change the clinical management of this disease in the near future.
{"title":"The many pathways driving liver inflammation in MASH","authors":"Herbert Tilg, Timon E. Adolph, Stefano Romeo, Rohit Loomba","doi":"10.1016/j.cmet.2026.02.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.02.018","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, affecting one-third of the global population. Most patients exhibit simple steatosis, whereas up to 20% develop metabolic dysfunction-associated steatohepatitis (MASH), potentially culminating in liver cirrhosis and hepatocellular carcinoma. Diverse parallel mechanisms contribute to the development of MASH, which are fueled by hepatic lipotoxicity, intestinal dysbiosis, and pro-inflammatory diets shaping innate and adaptive immune responses. Moreover, adipose tissue is driving systemic inflammation in obesity, contributing to the inflammatory burden in obesity-related MASH. Polygenetic and multiomic risk scores identify distinct types of MASLD with dominant aggressive liver disease or extrahepatic cardiometabolic disease. Here, we review the complexity of multiple parallel inflammatory hits in MASH and delineate that most current MASH drugs exert pleiotropic metabolic and anti-inflammatory properties. These new therapies will change the clinical management of this disease in the near future.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"13 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-23DOI: 10.1016/j.cmet.2026.02.016
Ayaka Sugiura, Katherine L. Beier, Channing Chi, Darren R. Heintzman, Xiang Ye, Melissa M. Wolf, Andrew R. Patterson, Jacqueline-Yvonne Cephus, Hanna S. Hong, Jeffrey M. Perera, Costas A. Lyssiotis, Dawn C. Newcomb, Jeffrey C. Rathmell
{"title":"Tissue and CD4 T cell subset dependence on the amino acid transporter SLC38A1","authors":"Ayaka Sugiura, Katherine L. Beier, Channing Chi, Darren R. Heintzman, Xiang Ye, Melissa M. Wolf, Andrew R. Patterson, Jacqueline-Yvonne Cephus, Hanna S. Hong, Jeffrey M. Perera, Costas A. Lyssiotis, Dawn C. Newcomb, Jeffrey C. Rathmell","doi":"10.1016/j.cmet.2026.02.016","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.02.016","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"71 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147501748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-23DOI: 10.1016/j.cmet.2026.02.017
Mark A. Febbraio, Bente Klarlund Pedersen
In a little over 100 years, global life expectancy has increased by ∼60%. Paradoxically, it has been estimated that we now exercise five times less than we did 100 years ago. Despite a marked increase in life expectancy, the prevalence of non-contagious diseases (NCDs), otherwise known as “chronic lifestyle diseases,” such as cardiovascular disease, type 2 diabetes, cognitive diseases, and cancer, has increased. Here, we discuss the concept of “exercise as medicine” for the treatment of NCD and provide evidence for the direct mechanisms by which regular physical activity can either prevent the onset or slow the progression of these diseases.
{"title":"Exercise as a therapeutic intervention for long-lasting and chronic diseases","authors":"Mark A. Febbraio, Bente Klarlund Pedersen","doi":"10.1016/j.cmet.2026.02.017","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.02.017","url":null,"abstract":"In a little over 100 years, global life expectancy has increased by ∼60%. Paradoxically, it has been estimated that we now exercise five times less than we did 100 years ago. Despite a marked increase in life expectancy, the prevalence of non-contagious diseases (NCDs), otherwise known as “chronic lifestyle diseases,” such as cardiovascular disease, type 2 diabetes, cognitive diseases, and cancer, has increased. Here, we discuss the concept of “exercise as medicine” for the treatment of NCD and provide evidence for the direct mechanisms by which regular physical activity can either prevent the onset or slow the progression of these diseases.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"92 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Proteomics enables the systematic elucidation of biological mechanisms underlying frailty. Through a large proteome-wide association study of 2,911 plasma proteins from 50,506 UK Biobank participants, we identified 1,339 proteins significantly associated with frailty, highlighting collagen-containing extracellular matrix and vesicle lumen pathways. Replication in the TwinGene study confirmed partial but consistent associations. Mendelian randomization analyses identified five potentially causal proteins for frailty. Moreover, we developed a proteomic frailty score (PFS) that showed strong predictive performance for 199 incident diseases across 13 categories and broad responsiveness to 84 modifiable risk factors. Longitudinal analyses revealed accelerated PFS progression with advancing age and increasing baseline frailty severity. An online tool (https://zipoa.shinyapps.io/frailty/) was created for public PFS calculation. Finally, we observed a biphasic pattern of frailty-associated proteomic dysregulation across the lifespan, with peaks at ages ∼50 and ∼63. Together, we establish PFS as a biomarker of biological aging while identifying critical windows and molecular targets for frailty interventions.
{"title":"Plasma proteomic signature of frailty in 50,506 adults","authors":"Xueqing Jia, Weijing Gao, Hampus Hagelin, Yanjie Zhao, Jingyun Zhang, Xingqi Cao, Liming Zhang, Youheng Wu, Lina Ma, Liangkai Chen, Liang Sun, Huan Guo, Cuntai Zhang, Juulia Jylhävä, Zixin Hu, Emiel O. Hoogendijk, Sara Hägg, Zuyun Liu","doi":"10.1016/j.cmet.2026.02.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.02.013","url":null,"abstract":"Proteomics enables the systematic elucidation of biological mechanisms underlying frailty. Through a large proteome-wide association study of 2,911 plasma proteins from 50,506 UK Biobank participants, we identified 1,339 proteins significantly associated with frailty, highlighting collagen-containing extracellular matrix and vesicle lumen pathways. Replication in the TwinGene study confirmed partial but consistent associations. Mendelian randomization analyses identified five potentially causal proteins for frailty. Moreover, we developed a proteomic frailty score (PFS) that showed strong predictive performance for 199 incident diseases across 13 categories and broad responsiveness to 84 modifiable risk factors. Longitudinal analyses revealed accelerated PFS progression with advancing age and increasing baseline frailty severity. An online tool (<ce:inter-ref xlink:href=\"https://zipoa.shinyapps.io/frailty/\" xlink:type=\"simple\">https://zipoa.shinyapps.io/frailty/</ce:inter-ref>) was created for public PFS calculation. Finally, we observed a biphasic pattern of frailty-associated proteomic dysregulation across the lifespan, with peaks at ages ∼50 and ∼63. Together, we establish PFS as a biomarker of biological aging while identifying critical windows and molecular targets for frailty interventions.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"21 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-16DOI: 10.1016/j.cmet.2026.02.009
Min Seo Kim, Qiuli Chen, Yang Sui, Xiong Yang, Shaoqi Wang, Lu-Chen Weng, So Mi Jemma Cho, Satoshi Koyama, Xinyu Zhu, Kang Yu, Xingyu Chen, Rufan Zhang, Wanqing Yin, Shuangqiao Liao, Zhaoqi Liu, Fowzan S. Alkuraya, Pradeep Natarajan, Patrick T. Ellinor, Akl C. Fahed, Minxian Wang
Obesity and type 2 diabetes (T2D) are metabolic diseases with shared pathophysiology. Traditional polygenic risk scores (PRSs) have focused on these conditions individually, yet the single-disease approach falls short in capturing the full dimension of metabolic dysfunction. We derived a biologically enriched metabolic PRS (MetPRS), a composite score that uses multi-ancestry genome-wide association studies of 20 metabolic traits from over 8.5 million individuals. MetPRS, optimized to predict obesity (O-MetPRS) and T2D (D-MetPRS), outperformed existing PRSs in predicting obesity and T2D across six ancestries. O-MetPRS and D-MetPRS effectively identify individuals at high risk for metabolic multimorbidity and predict clinical outcomes, including GLP-1 receptor agonist initiation. O-MetPRS and D-MetPRS showed an ∼2-fold increased risk of GLP-1 receptor agonist initiation for the top decile versus the middle quintile. The biologically enriched MetPRS has the potential to add an extra layer of information to disease prediction and management approaches for metabolic diseases.
{"title":"Metabolic polygenic risk scores for prediction of obesity, type 2 diabetes, and related morbidities","authors":"Min Seo Kim, Qiuli Chen, Yang Sui, Xiong Yang, Shaoqi Wang, Lu-Chen Weng, So Mi Jemma Cho, Satoshi Koyama, Xinyu Zhu, Kang Yu, Xingyu Chen, Rufan Zhang, Wanqing Yin, Shuangqiao Liao, Zhaoqi Liu, Fowzan S. Alkuraya, Pradeep Natarajan, Patrick T. Ellinor, Akl C. Fahed, Minxian Wang","doi":"10.1016/j.cmet.2026.02.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.02.009","url":null,"abstract":"Obesity and type 2 diabetes (T2D) are metabolic diseases with shared pathophysiology. Traditional polygenic risk scores (PRSs) have focused on these conditions individually, yet the single-disease approach falls short in capturing the full dimension of metabolic dysfunction. We derived a biologically enriched metabolic PRS (MetPRS), a composite score that uses multi-ancestry genome-wide association studies of 20 metabolic traits from over 8.5 million individuals. MetPRS, optimized to predict obesity (O-MetPRS) and T2D (D-MetPRS), outperformed existing PRSs in predicting obesity and T2D across six ancestries. O-MetPRS and D-MetPRS effectively identify individuals at high risk for metabolic multimorbidity and predict clinical outcomes, including GLP-1 receptor agonist initiation. O-MetPRS and D-MetPRS showed an ∼2-fold increased risk of GLP-1 receptor agonist initiation for the top decile versus the middle quintile. The biologically enriched MetPRS has the potential to add an extra layer of information to disease prediction and management approaches for metabolic diseases.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"95 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The protein-level functionalities of the human gut microbiota in large populations, and their associations with host factors, remain unexplored. This study reports a metaproteomic study of 1,967 fecal samples from 1,399 middle-aged and elderly Chinese individuals, identifying microbial functions linked to 44 phenotypes. We uncover aging-associated functional shifts in carbon metabolism and energy production driven by species within the Bacillota, Bacteroidota, Actinomycetota, and Pseudomonadota. Across metabolic diseases, we observe the consistent depletion of Bacillota species and their proteins involved in carbohydrate, energy, amino acid metabolism, and short-chain fatty acid production. We also identify medication-associated features across diabetes, hypertension, and dyslipidemia. Validated in an independent cohort, Megasphaera elsdenii emerged as a hub species in type 2 diabetes. Experimental validation indicates that M. elsdenii is promoted by antidiabetic drugs and may regulate glucose homeostasis through butyrate production. This study provides protein-level evidence of microbial functions in health and disease, highlighting potential therapeutic targets.
{"title":"Large-scale metaproteomics of human gut microbiota reveals microbial functions in metabolic diseases and aging","authors":"Shuang Liang, Yingying Sun, Zelei Miao, Bang-yan Li, Ziyuan Xing, Yuting Xie, Enci Cai, Sainan Li, Pu Liu, Min Yang, Menglei Shuai, Wanglong Gou, Wenhao Jiang, Youming Wang, Huanhuan Gao, Ke Zhang, Jing Yu, Xue Cai, Xingbing Wang, Yi Zhu, Yu-ming Chen, Ju-Sheng Zheng, Tiannan Guo","doi":"10.1016/j.cmet.2026.02.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.02.012","url":null,"abstract":"The protein-level functionalities of the human gut microbiota in large populations, and their associations with host factors, remain unexplored. This study reports a metaproteomic study of 1,967 fecal samples from 1,399 middle-aged and elderly Chinese individuals, identifying microbial functions linked to 44 phenotypes. We uncover aging-associated functional shifts in carbon metabolism and energy production driven by species within the Bacillota, Bacteroidota, Actinomycetota, and Pseudomonadota. Across metabolic diseases, we observe the consistent depletion of Bacillota species and their proteins involved in carbohydrate, energy, amino acid metabolism, and short-chain fatty acid production. We also identify medication-associated features across diabetes, hypertension, and dyslipidemia. Validated in an independent cohort, <em>Megasphaera elsdenii</em> emerged as a hub species in type 2 diabetes. Experimental validation indicates that <em>M. elsdenii</em> is promoted by antidiabetic drugs and may regulate glucose homeostasis through butyrate production. This study provides protein-level evidence of microbial functions in health and disease, highlighting potential therapeutic targets.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"100 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aging is associated with oxidative stress, but specific druggable pathways remain elusive. Here, we define a conserved iron-lipid axis driving primate aging, termed “ferro-aging.” Multi-tissue profiling in humans and non-human primates reveals age-progressive iron accumulation, fueling chronic lipid peroxidation orchestrated by acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4). Distinct from acute ferroptosis, this ACSL4-mediated process promotes cellular senescence and systemic functional decline. The therapeutic inhibition of hepatic ACSL4 via gene editing alleviates aging phenotypes in mice. Through functional screening and target engagement studies, we identify vitamin C (VC) as a direct inhibitor of ACSL4. Long-term VC administration in aged monkeys for over 40 months potently reduces ferro-aging signatures across tissues, attenuates multi-organ pathology, and improves neurological and metabolic functions. Multi-omic aging clocks indicate the VC-mediated reversal of biological age. Our work establishes ferro-aging as a core, targetable mechanism of primate aging and positions VC as a translatable geroprotective strategy through ACSL4 inhibition.
{"title":"Vitamin C inhibits ACSL4 to alleviate ferro-aging in primates","authors":"Lixiao Liu, Zikai Zheng, Wanbang You, Peng Yang, Yifan Wen, Yicheng Qiao, Shuai Ma, Hui Zhang, Shuo Zhang, Gang Xu, Chencan Ma, Ao Tian, Mengmeng Jiang, Tongtong Zhang, Lingling Geng, Jingyi Li, Xiaoyan Sun, Feibo Wang, Muzhao Xiong, Yuanhan Yang, Guang-Hui Liu","doi":"10.1016/j.cmet.2026.02.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.02.010","url":null,"abstract":"Aging is associated with oxidative stress, but specific druggable pathways remain elusive. Here, we define a conserved iron-lipid axis driving primate aging, termed “ferro-aging.” Multi-tissue profiling in humans and non-human primates reveals age-progressive iron accumulation, fueling chronic lipid peroxidation orchestrated by acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4). Distinct from acute ferroptosis, this ACSL4-mediated process promotes cellular senescence and systemic functional decline. The therapeutic inhibition of hepatic ACSL4 via gene editing alleviates aging phenotypes in mice. Through functional screening and target engagement studies, we identify vitamin C (VC) as a direct inhibitor of ACSL4. Long-term VC administration in aged monkeys for over 40 months potently reduces ferro-aging signatures across tissues, attenuates multi-organ pathology, and improves neurological and metabolic functions. Multi-omic aging clocks indicate the VC-mediated reversal of biological age. Our work establishes ferro-aging as a core, targetable mechanism of primate aging and positions VC as a translatable geroprotective strategy through ACSL4 inhibition.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"15 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-02DOI: 10.1016/j.cmet.2026.01.021
Yajun Tang, Junliang Kuang, Xixi Xia, Changliang Yao, Zile Zhou, Jiajian Liu, Zhenxing Ren, Keke Ding, Mengci Li, Yang Li, Fuxin Jiao, Dan Zheng, Tianlu Chen, Aihua Zhao, Xinjian Wan, Guang Ji, Shan Zhang, Xiaojiao Zheng, Wei Jia
The progression from metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) entails rapid, often irreversible hepatic injury, underscoring the urgent need for innovative therapeutic strategies. Here, we demonstrate that excessive dietary sugar intake, particularly fructose, exacerbates liver disease progression through microbiota-mediated amplification of endogenous acetaldehyde production. Analysis of over 210,000 participants from the UK Biobank revealed a dose-dependent correlation between sugar consumption and liver-related mortality, accompanied by a microbial shift favoring acetaldehyde/ethanol fermentation pathways in MASH patients. Mechanistically, gut-derived acetaldehyde activates hepatic stellate cells via upregulation of matrix metalloproteinase-7 (MMP7), driving fibrogenesis. To mitigate this, we engineered Ligilactobacillus salivarius HAM, a probiotic strain with enhanced acetaldehyde-degrading capacity, which effectively halted fibrosis progression in preclinical models of diet-induced liver disease. These findings highlight microbiota-targeted modulation of aldehyde metabolism as a promising therapeutic avenue to intercept the transition from MASLD to MASH.
{"title":"Targeting microbiota-generated acetaldehyde to prevent progression of metabolic dysfunction-associated steatotic liver disease","authors":"Yajun Tang, Junliang Kuang, Xixi Xia, Changliang Yao, Zile Zhou, Jiajian Liu, Zhenxing Ren, Keke Ding, Mengci Li, Yang Li, Fuxin Jiao, Dan Zheng, Tianlu Chen, Aihua Zhao, Xinjian Wan, Guang Ji, Shan Zhang, Xiaojiao Zheng, Wei Jia","doi":"10.1016/j.cmet.2026.01.021","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.01.021","url":null,"abstract":"The progression from metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) entails rapid, often irreversible hepatic injury, underscoring the urgent need for innovative therapeutic strategies. Here, we demonstrate that excessive dietary sugar intake, particularly fructose, exacerbates liver disease progression through microbiota-mediated amplification of endogenous acetaldehyde production. Analysis of over 210,000 participants from the UK Biobank revealed a dose-dependent correlation between sugar consumption and liver-related mortality, accompanied by a microbial shift favoring acetaldehyde/ethanol fermentation pathways in MASH patients. Mechanistically, gut-derived acetaldehyde activates hepatic stellate cells via upregulation of matrix metalloproteinase-7 (MMP7), driving fibrogenesis. To mitigate this, we engineered <em>Ligilactobacillus salivarius</em> HAM, a probiotic strain with enhanced acetaldehyde-degrading capacity, which effectively halted fibrosis progression in preclinical models of diet-induced liver disease. These findings highlight microbiota-targeted modulation of aldehyde metabolism as a promising therapeutic avenue to intercept the transition from MASLD to MASH.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147329820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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