{"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}
Cell metabolismPub 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
{"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}
{"title":"Neuroimmunometabolic co-evolution in the tumor micro- and macroenvironment","authors":"Yu Zhang, Weijie Zhuang, Haodong Zhu, Fansheng Meng, Mingtao Chen, Yibo Guo, Jia Fan, Yunfan Sun, Tong Ji","doi":"10.1016/j.cmet.2026.02.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.02.001","url":null,"abstract":"The nervous system integrates immune, endocrine, and circulatory systems to coordinate complex physiological responses. It influences tumor progression and treatment resistance through interactions with cancer cells and immune cells and by regulating metabolic processes within both the tumor microenvironment (TME) and tumor macroenvironment (TMaE). This review provides a comprehensive overview of the neuroimmunometabolic co-evolution within the TME and TMaE. At the TME scale, we discuss the role of the peripheral nervous system (PNS), including sympathetic, parasympathetic, and sensory neurons, in regulating metabolic processes and immune cell functions. At the TMaE scale, we highlight how cancer cells exploit brain-body interactions to reprogram systemic metabolism and immune responses, creating conditions that favor tumor progression. Additionally, we describe how the PNS serves as a conduit for long-range communication between tumors and distant organs. Finally, we identify key knowledge gaps, propose strategies to address current limitations, and discuss clinically actionable neuroimmune and neurometabolic therapies.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"52 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147319439","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 : 2026-02-23DOI: 10.1016/j.cmet.2026.01.016
Eva Novoa, Tamara Parracho, Julica Inderhees, Amaia Rodriguez, Cristina Riobello, Jose Iglesias-Moure, Anabel Fernández-Iglesias, Sara Martinez-Martinez, Ana Senra, Samuel Seoane, Marcos Fondevila, Cristina Iglesias, Alba Cabaleiro, Natalia da Silva Lima, Valentina Dorta, Borja López-Picallo, Lucia Ramos-Lage, Ashwin Woodhoo, Miguel Fidalgo, Maria L. Martínez-Chantar, Ruben Nogueiras
{"title":"Lack of PCK1 in hepatic stellate cells causes liver fibrosis by fueling tricarboxylic acid cycle and increasing glycolysis","authors":"Eva Novoa, Tamara Parracho, Julica Inderhees, Amaia Rodriguez, Cristina Riobello, Jose Iglesias-Moure, Anabel Fernández-Iglesias, Sara Martinez-Martinez, Ana Senra, Samuel Seoane, Marcos Fondevila, Cristina Iglesias, Alba Cabaleiro, Natalia da Silva Lima, Valentina Dorta, Borja López-Picallo, Lucia Ramos-Lage, Ashwin Woodhoo, Miguel Fidalgo, Maria L. Martínez-Chantar, Ruben Nogueiras","doi":"10.1016/j.cmet.2026.01.016","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.01.016","url":null,"abstract":"Phosphoenolpyruvate carboxykinase 1 (PCK1) is a key integrator of hepatic energy metabolism, but its role in hepatic stellate cells (HSCs), the main fibrogenic cells in the liver, remains unknown. We found that PCK1 is reduced in HSCs from fibrotic animals and people with fibrosis, correlating negatively with fibrosis severity. Silencing PCK1 activates human HSCs and increases fibrotic markers, whereas ectopic PCK1 expression blunts transforming growth factor β1 (TGF-β1)-induced activation. Activated HSCs show elevated glycolysis and tricarboxylic acid (TCA) cycle activity, but PCK1 overexpression reduces acetyl-coenzyme A (CoA), limiting TCA cycle intermediates and ameliorating HSC activation. In mice, HSC-specific PCK1 loss accelerates diet-induced liver fibrosis. Notably, mice lacking PCK1 in HSCs also develop spontaneous fibrosis on a normal diet. These findings show that disrupted cataplerosis from PCK1 loss enhances glycolysis and activates HSCs, promoting liver fibrosis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"5 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147279219","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 : 2026-02-20DOI: 10.1016/j.cmet.2026.01.020
Karl Wessendorf-Rodriguez, Maureen L. Ruchhoeft, Christopher W. Murray, Yale Huang, Ethan L. Ashley, Hector M. Galvez, Grace H. McGregor, Shrikaar Kambhampati, Reuben J. Shaw, Christian M. Metallo
{"title":"Modeling lipid homeostasis using stable isotope tracing and flux analysis","authors":"Karl Wessendorf-Rodriguez, Maureen L. Ruchhoeft, Christopher W. Murray, Yale Huang, Ethan L. Ashley, Hector M. Galvez, Grace H. McGregor, Shrikaar Kambhampati, Reuben J. Shaw, Christian M. Metallo","doi":"10.1016/j.cmet.2026.01.020","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.01.020","url":null,"abstract":"Lipids enable compartmentation and coordinate membrane-localized signaling events in cells, and dysregulation of lipid metabolism is linked to many disease states. However, limited tools are available for quantifying metabolic fluxes across the lipidome. To measure fluxes encompassing lipid homeostasis in cells and tissue slices, we apply stable isotope tracing, liquid chromatography-high-resolution mass spectrometry, and network-based isotopologue modeling to non-small cell lung cancer (NSCLC) models. Lipid metabolic flux analysis (Lipid-MFA) enables quantitation of fatty acid synthesis, elongation, headgroup assembly, and salvage reactions within virtually any biological system. Using Lipid-MFA, we observed decreased fatty acid synthase and very long-chain fatty acid (VLCFA) elongation fluxes, along with increased sphingolipid recycling, in p53-deficient versus liver kinase B1 (LKB1)-deficient NSCLC tumors using precision-cut lung slice culture. We also apply Lipid-MFA to demonstrate the unique trafficking of ceramides with distinct n-acyl chain lengths, highlighting the utility of this approach in elucidating molecular mechanisms in lipid homeostasis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"2 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146231293","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 : 2026-02-19DOI: 10.1016/j.cmet.2026.01.019
Yolanda Martí-Mateos, Zohreh Safari, Shaun Bevers, Ayush D. Midha, Will R. Flanigan, Tej Joshi, Helen Huynh, Brandon R. Desousa, Skyler Y. Blume, Alan H. Baik, Stephen Rogers, Aaron V. Issaian, Allan Doctor, Angelo D’Alessandro, Isha H. Jain
{"title":"Red blood cells serve as a primary glucose sink to improve glucose tolerance at altitude","authors":"Yolanda Martí-Mateos, Zohreh Safari, Shaun Bevers, Ayush D. Midha, Will R. Flanigan, Tej Joshi, Helen Huynh, Brandon R. Desousa, Skyler Y. Blume, Alan H. Baik, Stephen Rogers, Aaron V. Issaian, Allan Doctor, Angelo D’Alessandro, Isha H. Jain","doi":"10.1016/j.cmet.2026.01.019","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.01.019","url":null,"abstract":"High-altitude conditions improve glucose tolerance and reduce diabetes risk, but the physiological mechanism is not well understood. Using mouse models, we found that hypoxia alone robustly improved glucose tolerance and that the effect persisted for weeks after returning to normal oxygen levels. PET/CT imaging suggested a significant, unknown glucose sink beyond major internal organs. We hypothesized that hypoxia-induced red blood cells (RBCs) serve as this sink. Manipulating RBC numbers through phlebotomy or transfusion directly altered blood glucose, establishing RBCs as necessary and sufficient for this effect. In chronic hypoxia, RBCs showed a sustained ∼3-fold increase in glucose uptake and ∼2-fold increase in GLUT1 protein abundance, specifically in newly synthesized RBCs, which ultimately contributes to increased glycolytic flux toward 2,3-diphosphoglycerate (2,3-DPG). Mechanistically, acute hypoxia displaces GAPDH from inhibitory band 3 binding through competitive interactions with deoxyhemoglobin, thereby boosting glycolytic flux and driving 2,3-DPG production. We also found that hypoxia or our small-molecule hypoxia mimetic, HypoxyStat, rescued hyperglycemia in mouse models of type 1 and type 2 diabetes. Our findings identify RBCs as key regulators of systemic glucose metabolism, highlighting a novel therapeutic approach for hyperglycemic disorders.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"57 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146223274","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 : 2026-02-18DOI: 10.1016/j.cmet.2026.01.014
Jitendra Kumar, Yoshinori Takashima, Jose Morales, Brandon Wong, Lina Werner, Isabel N. Goronzy, Selene Rubino, Robert T. Trousdale, Gerald J. Berry, Jörg J. Goronzy, Cornelia M. Weyand
{"title":"Lipid droplet-induced T cell death sustains autoimmune tissue inflammation","authors":"Jitendra Kumar, Yoshinori Takashima, Jose Morales, Brandon Wong, Lina Werner, Isabel N. Goronzy, Selene Rubino, Robert T. Trousdale, Gerald J. Berry, Jörg J. Goronzy, Cornelia M. Weyand","doi":"10.1016/j.cmet.2026.01.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.01.014","url":null,"abstract":"Autoimmunity leading to rheumatoid arthritis (RA) involves CD4<sup>+</sup> T cell recruitment into synovial tissue. However, metabolic conditions supporting the survival and pro-inflammatory effector functions of these tissue-invading T cells remain poorly understood. Lipidomic analysis identified the inflamed synovium as a lipid-rich environment. In functional studies, administration of the free fatty acid oleic acid exacerbated synovitis. Tissue-invading CD4<sup>+</sup> T cells responded to fatty acid with rapid cell lysis, releasing cytoplasmic and nuclear content into the extracellular space. This T cell lytic death required sequestration of the pore-forming molecule gasdermin D and the acyltransferase zDHHC5 to lipid droplets, which translocated to the plasma membrane to trigger membrane rupture and pyroptotic cell death. Targeting lipid droplet formation in CD4<sup>+</sup> T cells through perilipin-2 knockdown or inhibiting gasdermin activation by blocking protein acylation proved highly effective in suppressing synovitis. Thus, autoimmune CD4<sup>+</sup> T cells lack metabolic resilience, are primed to undergo pyroptosis in lipid-rich environments, and deliver pro-inflammatory cargo to surrounding tissue.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"48 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146209018","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 : 2026-02-17DOI: 10.1016/j.cmet.2026.01.012
Iñigo Chivite, Erika Monelli, Margalida Munar-Gelabert, Alicia G. Gómez-Valadés, Abdiel Alvarado-Diaz, Macarena Pozo, Luis Varela, Sara Ramírez, Roberta Haddad-Tóvolli, Miriam Toledo, Júlia Fos-Domènech, Francisco Díaz-Castro, Iasim Tahiri, Pau García-Ramón, Mariana Ferreira, Chloé van Gelder, Anne Abot, Óscar Osorio-Conles, José Antonio Valer, Arnaud Obri, Marc Claret
{"title":"Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice","authors":"Iñigo Chivite, Erika Monelli, Margalida Munar-Gelabert, Alicia G. Gómez-Valadés, Abdiel Alvarado-Diaz, Macarena Pozo, Luis Varela, Sara Ramírez, Roberta Haddad-Tóvolli, Miriam Toledo, Júlia Fos-Domènech, Francisco Díaz-Castro, Iasim Tahiri, Pau García-Ramón, Mariana Ferreira, Chloé van Gelder, Anne Abot, Óscar Osorio-Conles, José Antonio Valer, Arnaud Obri, Marc Claret","doi":"10.1016/j.cmet.2026.01.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.01.012","url":null,"abstract":"Endothelial cells (ECs) are key metabolic gatekeepers, yet their role in metabolic health remains unclear. Given their central involvement in energy metabolism, mitochondria are ideally positioned to enable ECs to adapt to ever-changing metabolic requirements. Here, we explore the hypothesis that mitochondrial dynamics proteins in ECs influence whole-body metabolic status. Genetic deficiency of <em>Mfn2</em> in ECs (<em>Mfn2</em><sup><em>iΔEC</em></sup>), but not of <em>Mfn1</em><sup><em>iΔEC</em></sup>, induces a mitohormetic response in the adipose vasculature, enhancing antioxidant defenses, mitochondrial fitness, and lipid oxidation, ultimately improving metabolic outcomes. Cultured ECs secrete the mitokine growth differentiation factor 15 (GDF15) via a forkhead box O1 (FOXO1)-dependent axis, a response also observed under stress conditions <em>in vivo</em>. Notably, <em>Mfn2</em><sup><em>iΔEC</em></sup> mice exhibited elevated endothelial and circulating GDF15 levels, and neutralization of GDF15 partly attenuated their metabolic benefits. Consistent with mitohormetic activation, <em>Mfn2</em><sup><em>iΔEC</em></sup> mice showed protection against diet-induced obesity and delayed age-related decline. Hence, vascular mitohormetic adaptations emerge as a novel mechanism promoting systemic metabolic health.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"118 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146209019","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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