Cell metabolismPub Date : 2026-09-22DOI: 10.1016/j.cmet.2026.08.023
Sangmin Yong,Hyewon Jo,Geunho Yook,Jihyeon Park,Minju Kim,Sunwoo Kang,Jiyeon Shin,Donghyun Kang,Tae Woo Kim,Moon Jong Chang,Chong Bum Chang,Seung-Baik Kang,Yong-ho Lee,Byeong Jae Lee,Dolph L. Hatfield,Yi-Jun Kim,Jin-Hong Kim
{"title":"A liver-cartilage selenium axis underlies metabolic comorbidity in osteoarthritis","authors":"Sangmin Yong,Hyewon Jo,Geunho Yook,Jihyeon Park,Minju Kim,Sunwoo Kang,Jiyeon Shin,Donghyun Kang,Tae Woo Kim,Moon Jong Chang,Chong Bum Chang,Seung-Baik Kang,Yong-ho Lee,Byeong Jae Lee,Dolph L. Hatfield,Yi-Jun Kim,Jin-Hong Kim","doi":"10.1016/j.cmet.2026.08.023","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.08.023","url":null,"abstract":"While osteoarthritis (OA) has traditionally been viewed as a localized joint disorder, systemic metabolic dysfunction is increasingly recognized as a key contributor to its pathogenesis. Here, we identify a liver-cartilage micronutrient axis in which hepatic dysfunction promotes OA through impaired selenium (Se) metabolism. Nationwide cohorts reveal elevated OA prevalence among individuals with liver disease. In murine models of acute and chronic liver injury and metabolic dysfunction-associated steatohepatitis (MASH), hepatic dysfunction disrupts the selenoprotein P (SELENOP)-ApoER2 axis, compromising Se delivery to cartilage. Mechanistically, hepatic stress reduces hepatocyte SELENOP output through convergent transcriptional repression and translational suppression via ribosome collision on selenocysteine (Sec)-rich SELENOP transcripts. The resulting cartilage selenoprotein deficiency promotes chondrocyte senescence, exacerbating OA. Inorganic Se supplementation bypasses impaired SELENOP-mediated Se delivery, restoring chondrocyte selenoproteins and alleviating OA, highlighting Se as a nutritionally modifiable factor. Our findings suggest preventive strategies against joint comorbidity in the growing population with metabolic liver disease.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"4 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149013587","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}
Cell metabolismPub Date : 2026-09-18DOI: 10.1016/j.cmet.2026.08.018
Keisuke Sawada,Jarren R. Oates,Masaki Kimura,Traci E. Stankiewicz,John Eom,Pablo C. Alarcon,Hak Chung,Michelle S.M.A. Damen,Cassidy J. Ulanowicz,Jennifer L. Wayland,Ethan S.O. Williams Fonner,Colin C. Anderson,Hayde K. Cuervo-Jimenez,Amelia M. Pearson,Yunguan Wang,Nathan Salomonis,Ty D. Troutman,Julie A. Reisz,Jeffrey C. Rathmell,Sara Szabo,Michael A. Helmrath,Takanori Takebe,Maria E. Moreno-Fernandez,Senad Divanovic
{"title":"Glutamine metabolism as a rheostat of CD4+ T cell pathogenic function in metabolic dysfunction-associated steatotic liver disease","authors":"Keisuke Sawada,Jarren R. Oates,Masaki Kimura,Traci E. Stankiewicz,John Eom,Pablo C. Alarcon,Hak Chung,Michelle S.M.A. Damen,Cassidy J. Ulanowicz,Jennifer L. Wayland,Ethan S.O. Williams Fonner,Colin C. Anderson,Hayde K. Cuervo-Jimenez,Amelia M. Pearson,Yunguan Wang,Nathan Salomonis,Ty D. Troutman,Julie A. Reisz,Jeffrey C. Rathmell,Sara Szabo,Michael A. Helmrath,Takanori Takebe,Maria E. Moreno-Fernandez,Senad Divanovic","doi":"10.1016/j.cmet.2026.08.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.08.018","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) severity is independently linked with pathogenic CD4+ T cell responses and skewed hepatic glutamine (Gln) metabolism. Whether these processes interact to drive disease progression remains unclear. Here, we identify hepatic Gln depletion as a key feature of steatohepatitis that is linked with increased hepatic CD4+ T cell inflammation and hepatocellular damage in humans. In complementary mouse models, both total hepatic and hepatic CD4+ T cell Gln levels were similarly reduced. Restoration of hepatic Gln through supplementation selectively restrained hepatic CD4+ T cell inflammatory programs and alleviated hepatocellular damage and disease severity. Mechanistically, T cell-intrinsic Gls1-mediated glutaminolysis limited O-GlcNAcylation to dampen pathogenic CD4+ T cell inflammation. Importantly, Gln treatment dampened CD4+ T cell-mediated injury in human liver organoids. Together, these findings establish hepatic CD4+ T cell-intrinsic Gln metabolism as a critical rheostat of pathogenic inflammation in MASLD and invoke metabolism-targeted strategies to restrict disease progression.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"2 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993809","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}
{"title":"Zonated cholesterol sensing by SIRT2 drives MASLD-HCC","authors":"Yingting Zhang,Xidai Long,Yinkun Fu,Xinxin Tang,Hao Luo,Zhihui Zou,Wei He,Longchuan Han,Yue Li,Jing Luo,Lihong Tian,Yuheng Lu,Yi Chen,Riming Pan,Xinyu Bao,Yurui Luo,Zonglin Huang,Zhenwu Zhang,Yonghui Liu,Li Feng,Ying Huang,Chao-Po Lin,Jian Zhang,Guoqiang Chen,Ming He","doi":"10.1016/j.cmet.2026.08.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.08.015","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC), but how metabolic zonation drives regional transformation remains unclear. We identify sirtuin 2 (SIRT2) as a zonated cholesterol sensor that initiates reprogramming to drive MASLD-HCC. Lineage tracing establishes zone 1 hepatocytes as the cellular origin of tumors. SIRT2 overexpression in zone 1 triggers HCC, whereas its deletion prevents carcinogenesis by restoring cholesterol and bile acid metabolism and CD8+ T cell recruitment. Mechanistically, cholesterol binds and activates SIRT2, which deacetylates sterol carrier protein 2 (SCP2) at Lys546, thereby blocking peroxisome proliferator-activated receptor α (PPARα) recruitment to the Cyp7b1 promoter, suppressing alternative bile acid synthesis, and permitting 27-hydroxycholesterol accumulation. SIRT2 inhibition reverses this cascade in mice and human hepatic organoids. Patient specimens confirm zonal SIRT2 and cytochrome P450 7B1 (CYP7B1) dysregulation. Our findings establish spatially compartmentalized cholesterol sensing as a new regulatory layer and identify SIRT2 as a druggable target in liver cancer.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"10 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148980622","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}
Cell metabolismPub Date : 2026-09-12DOI: 10.1016/j.cmet.2026.09.002
Xiaohua Su,Young Jin Gi,Deepavali Chakravarti,Io Long Chan,Aijun Zhang,Xuefeng Xia,Kenneth Y. Tsai,Elsa R. Flores
{"title":"TAp63 Is a Master Transcriptional Regulator of Lipid and Glucose Metabolism","authors":"Xiaohua Su,Young Jin Gi,Deepavali Chakravarti,Io Long Chan,Aijun Zhang,Xuefeng Xia,Kenneth Y. Tsai,Elsa R. Flores","doi":"10.1016/j.cmet.2026.09.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.09.002","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"18 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148946587","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}
Cell metabolismPub Date : 2026-09-10DOI: 10.1016/j.cmet.2026.08.014
Selim Chaib,Larissa G.P. Langhi Prata,Masayoshi Suda,Andres Sola,Thomas J. Mitchell,Zacharias P. Anastasiadis,Hawley E. Kunz,Jia Nie,Stella G. Victorelli,Ricardo Lozano Flores,Moritz Weigl,Shimpei Kawamoto,Ken Uemura,Hyungsoo Kim,Binsheng Wang,Christina L. Inman,Tamar Pirtskhalava,Nino Giorgadze,Ailing Xue,Kurt O. Johnson,Jair M. Espindola-Netto,Sonja Suvakov,Jennet Hatamova,Erik S. Parker,Davyn Benitto Hartono,Vagisha Kulshreshtha,Jose Alberto Lopez-Dominguez,Aaron M. Deisinger,Allyson K. Palmer,Yi Zhu,Megan M. Weivoda,Anne Gingery,Robert Hromas,Vesna D. Garovic,João F. Passos,David B. Allison,Eiji Hara,Michael D. Jensen,Nicolas Musi,Stefan G. Tullius,Ze’ev A. Ronai,Manuel Serrano,Ming Xu,Ian R. Lanza,Yuji Ikeno,Tamara Tchkonia,James L. Kirkland
{"title":"Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction","authors":"Selim Chaib,Larissa G.P. Langhi Prata,Masayoshi Suda,Andres Sola,Thomas J. Mitchell,Zacharias P. Anastasiadis,Hawley E. Kunz,Jia Nie,Stella G. Victorelli,Ricardo Lozano Flores,Moritz Weigl,Shimpei Kawamoto,Ken Uemura,Hyungsoo Kim,Binsheng Wang,Christina L. Inman,Tamar Pirtskhalava,Nino Giorgadze,Ailing Xue,Kurt O. Johnson,Jair M. Espindola-Netto,Sonja Suvakov,Jennet Hatamova,Erik S. Parker,Davyn Benitto Hartono,Vagisha Kulshreshtha,Jose Alberto Lopez-Dominguez,Aaron M. Deisinger,Allyson K. Palmer,Yi Zhu,Megan M. Weivoda,Anne Gingery,Robert Hromas,Vesna D. Garovic,João F. Passos,David B. Allison,Eiji Hara,Michael D. Jensen,Nicolas Musi,Stefan G. Tullius,Ze’ev A. Ronai,Manuel Serrano,Ming Xu,Ian R. Lanza,Yuji Ikeno,Tamara Tchkonia,James L. Kirkland","doi":"10.1016/j.cmet.2026.08.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.08.014","url":null,"abstract":"Senescent cells, which are normally cleared by the immune system but accumulate with age, contribute to multiple disorders including metabolic dysfunction and impaired fitness. While immune checkpoint inhibitors have been well studied in cancer, the role of programmed cell death ligand 2 (PD-L2) in non-cancerous, age-associated cellular senescence remains unclear. We found that PD-L2 is upregulated in isolated senescent human cells and during aging, and senolytics can remove age-associated, highly PD-L2-expressing senescent cells. Old PD-L2 knockout mice accumulate fewer senescent cells than old wild-type mice, and their insulin sensitivity and grip strength are greater. Anti-PD-L2 therapy restored insulin sensitivity in aged wild-type mice. PD-L2 acts as an immune checkpoint on senescent cells, allowing them to evade immune clearance and promoting their persistence during aging. Targeting PD-L2 in senescent cells may be a strategy for alleviating the age-related dysfunction associated with cellular senescence.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"31 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148915155","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}
Cell metabolismPub Date : 2026-09-08DOI: 10.1016/j.cmet.2026.08.013
Pawel Kordowitzki,Anju E. Joham,Clifford J. Rosen
{"title":"Implications of GLP-1 receptor agonists for the fertility of women with polyendocrine metabolic ovarian syndrome","authors":"Pawel Kordowitzki,Anju E. Joham,Clifford J. Rosen","doi":"10.1016/j.cmet.2026.08.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.08.013","url":null,"abstract":"Women with polyendocrine metabolic ovarian syndrome (PMOS) represent a particularly challenging patient population, characterized by the convergence of reproductive dysfunction, obesity, insulin resistance, and chronic inflammation. The emergence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) offers a transformative therapeutic opportunity, addressing the complex endocrine and reproductive disturbances that underpin this disorder.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"11 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148902523","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}
Cell metabolismPub Date : 2026-09-08DOI: 10.1016/j.cmet.2026.07.018
Elisabet Stener-Victorin,Han Zhao,Ricardo Azziz,Helena Teede
{"title":"A new name, an old crisis: Metabolic dysfunction at the core of polyendocrine metabolic ovarian syndrome","authors":"Elisabet Stener-Victorin,Han Zhao,Ricardo Azziz,Helena Teede","doi":"10.1016/j.cmet.2026.07.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.07.018","url":null,"abstract":"Affecting hundreds of millions of women worldwide, polyendocrine metabolic ovarian syndrome (PMOS, formerly polycystic ovary syndrome) carries a significantly higher risk of cardiovascular and metabolic diseases. Here we discuss how renaming this disease reframes a profoundly misunderstood condition for which basic metabolic research remains critically underfunded and fragmented.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"35 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148902526","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}
{"title":"Aging microenvironment induces CD8+ T cell exhaustion by suppressing hepatic β-hydroxybutyrylate synthesis","authors":"Yifeng Xiao,Yanling Zhang,Zihao Zhao,Zijian Zhang,Xiaohui Zhang,Pengju Chen,Jin Gu,Haichuan Zhu,Peng Jiang,Jie Cheng","doi":"10.1016/j.cmet.2026.08.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.08.009","url":null,"abstract":"The metabolic mechanisms by which aging blunts CD8+ T cell antitumor and pathogen defense remain unknown. We demonstrate that the aged microenvironment induces CD8+ T cell exhaustion by reducing β-hydroxybutyrate (3HB) bioavailability. Aging represses hepatic BDH1-dependent 3HB synthesis, restricting SLC16A1-mediated 3HB uptake. Hepatic BDH1 ablation recapitulates age-associated CD8+ T cell dysfunction, compromising antiviral and antitumor immunity, whereas 3HB supplementation reverses these deficits via protein β-hydroxybutyrylation. Using a 3HB-derived chemical probe, 3Halk, together with functional screening, we identify PRKAR1B as a primary effector of 3HB signaling. PRKAR1B β-hydroxybutyrylation inhibits the transcription factor cyclic AMP (cAMP)-responsive element modulator (CREM), which activates T cell exhaustion-related gene expression. Age-associated 3HB depletion enhances CREM-dependent transcription, sustaining CD8+ T cell exhaustion. Consistently, the aged microenvironment compromises chimeric antigen receptor (CAR) T antitumor activity, which is substantially restored by 3HB treatment. Collectively, this study uncovers a hepatic metabolism-derived 3HB-CREM axis governing CD8+ T cell immunosenescence, highlighting 3HB as a viable immunorestorative strategy to improve immunotherapy outcomes in aged individuals.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"43 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877367","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
