Social isolation is a major environmental driver of anxiety disorders, yet its neurobiological underpinnings remain elusive. We report here that social isolation triggers "ferroplasticity"-a novel form of experience-dependent synaptic remodeling-in ventral hippocampus (vHip) pyramidal neurons via a glucocorticoid-initiated iron-α-synuclein (α-Syn) axis. Psychosocial stress specifically engages this pathway. Mechanistically, isolation-induced glucocorticoid receptor activation upregulates transferrin receptor 1 (TfR1), leading to neuronal iron accumulation, which boosts α-Syn expression via translational derepression. α-Syn then enhances glutamate release and spine density, driving vHip hyperexcitability and anxiety. Interventions targeting the TfR1-iron-α-Syn axis at any node prevent or reverse anxiety-like behaviors, establishing necessity and causality. Translationally, intranasal delivery of an iron chelator or α-Syn-targeting antisense oligonucleotide (ASO) normalizes vHip neural activity and alleviates anxiety, highlighting a direct and viable path to clinical translation. Our findings define ferroplasticity as a core mechanism in social stress pathology, bridging brain iron metabolism with affective disorders.
{"title":"Ferroplasticity drives social isolation-induced anxiety via a ventral hippocampal iron-α-synuclein axis","authors":"Zhuo Wang, Sifan Yang, Tianrong Huang, Jinhui Zhao, Shuangyi Tan, Yuhan Zhang, Tianming Lü, Pingming Qiu, Junxia Min, Fudi Wang","doi":"10.1016/j.cmet.2025.12.022","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.12.022","url":null,"abstract":"Social isolation is a major environmental driver of anxiety disorders, yet its neurobiological underpinnings remain elusive. We report here that social isolation triggers \"ferroplasticity\"-a novel form of experience-dependent synaptic remodeling-in ventral hippocampus (vHip) pyramidal neurons via a glucocorticoid-initiated iron-α-synuclein (α-Syn) axis. Psychosocial stress specifically engages this pathway. Mechanistically, isolation-induced glucocorticoid receptor activation upregulates transferrin receptor 1 (TfR1), leading to neuronal iron accumulation, which boosts α-Syn expression via translational derepression. α-Syn then enhances glutamate release and spine density, driving vHip hyperexcitability and anxiety. Interventions targeting the TfR1-iron-α-Syn axis at any node prevent or reverse anxiety-like behaviors, establishing necessity and causality. Translationally, intranasal delivery of an iron chelator or α-Syn-targeting antisense oligonucleotide (ASO) normalizes vHip neural activity and alleviates anxiety, highlighting a direct and viable path to clinical translation. Our findings define ferroplasticity as a core mechanism in social stress pathology, bridging brain iron metabolism with affective disorders.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"17 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146072074","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 : 2026-01-26DOI: 10.1016/j.cmet.2025.12.018
Christina Papa, Alina Rose, Hugo N.G. Martin, Abibe Useini, Florian Geier, Longsheng Liao, Jesús Rafael Rodríguez-Aguilera, Philipp Valina-Allo, Anne Hoffmann, Andrey Tvardovskiy, Faiqa Zulfqar, Andrea Zimmerman, Gerda Schicht, Fritzi Ott, Christiane Körner, Beatrice Engelmann, Ulrike Rolle-Kampczyk, Martin von Bergen, Matthias Meier, Till Bartke, Daniel Seehofer, Nora Klöting, Madlen Matz-Soja, Georg Damm, Jes-Niels Boeckel, Joerg M. Buescher, Matthias Blüher, Ulrich Laufs, Olga Bondareva, Norbert Sträter, Georg Künze, John T. Heiker, Bilal N. Sheikh
{"title":"Bempedoic acid directly binds and activates PPARα","authors":"Christina Papa, Alina Rose, Hugo N.G. Martin, Abibe Useini, Florian Geier, Longsheng Liao, Jesús Rafael Rodríguez-Aguilera, Philipp Valina-Allo, Anne Hoffmann, Andrey Tvardovskiy, Faiqa Zulfqar, Andrea Zimmerman, Gerda Schicht, Fritzi Ott, Christiane Körner, Beatrice Engelmann, Ulrike Rolle-Kampczyk, Martin von Bergen, Matthias Meier, Till Bartke, Daniel Seehofer, Nora Klöting, Madlen Matz-Soja, Georg Damm, Jes-Niels Boeckel, Joerg M. Buescher, Matthias Blüher, Ulrich Laufs, Olga Bondareva, Norbert Sträter, Georg Künze, John T. Heiker, Bilal N. Sheikh","doi":"10.1016/j.cmet.2025.12.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.12.018","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"117 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048539","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 : 2026-01-22DOI: 10.1016/j.cmet.2025.12.013
Ariel J. Hernandez-Leyva, Amalia Z. Berna, Maggie H. Bui, Yang Liu, Anne L. Rosen, Michael A. Lint, Samantha A. Whiteside, Natalia Jaeger, Ryan T. McDonough, Nikhilesh Joardar, Jesús Santiago-Borges, Christopher P. Tomera, Wentai Luo, Audrey R. Odom John, Andrew L. Kau
The gut microbiota is crucial to health, yet implementation of microbiota-based therapeutics is limited by the lack of rapid diagnostics. We hypothesize that breath contains gut microbe-derived volatile organic compounds (VOCs) reflecting microbiota composition and metabolism. In healthy children, we found that breath VOC composition (or volatilome), assessed by gas chromatography-mass spectrometry, correlates with gut microbiome composition and function. By capturing exhaled breath from human-stool-colonized and monocolonized gnotobiotic mice, we profiled breath VOCs and discovered that murine breath is also significantly influenced by the gut microbiome. VOCs from cultured gut microbes were identified in vivo in monocolonized gnotobiotic colonized mice. As a proof of principle, we demonstrated that exhaled breath predicts the abundance of a disease-associated bacterium, Eubacterium siraeum, in children with asthma. Altogether, our studies identify microbe-derived VOCs in breath, show that gut bacterial metabolism directly contributes to mammalian breath VOC profiles, and inform the development of non-invasive microbiome diagnostics.
{"title":"The gut microbiota shapes the human and murine breath volatilome","authors":"Ariel J. Hernandez-Leyva, Amalia Z. Berna, Maggie H. Bui, Yang Liu, Anne L. Rosen, Michael A. Lint, Samantha A. Whiteside, Natalia Jaeger, Ryan T. McDonough, Nikhilesh Joardar, Jesús Santiago-Borges, Christopher P. Tomera, Wentai Luo, Audrey R. Odom John, Andrew L. Kau","doi":"10.1016/j.cmet.2025.12.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.12.013","url":null,"abstract":"The gut microbiota is crucial to health, yet implementation of microbiota-based therapeutics is limited by the lack of rapid diagnostics. We hypothesize that breath contains gut microbe-derived volatile organic compounds (VOCs) reflecting microbiota composition and metabolism. In healthy children, we found that breath VOC composition (or volatilome), assessed by gas chromatography-mass spectrometry, correlates with gut microbiome composition and function. By capturing exhaled breath from human-stool-colonized and monocolonized gnotobiotic mice, we profiled breath VOCs and discovered that murine breath is also significantly influenced by the gut microbiome. VOCs from cultured gut microbes were identified <em>in vivo</em> in monocolonized gnotobiotic colonized mice. As a proof of principle, we demonstrated that exhaled breath predicts the abundance of a disease-associated bacterium, <em>Eubacterium siraeum</em>, in children with asthma. Altogether, our studies identify microbe-derived VOCs in breath, show that gut bacterial metabolism directly contributes to mammalian breath VOC profiles, and inform the development of non-invasive microbiome diagnostics.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"268 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022153","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 : 2026-01-22DOI: 10.1016/j.cmet.2025.12.011
Katia Troha, Shrikaar Kambhampati, Arianna Insenga, Christian M. Metallo, Janelle S. Ayres
The immune system defends against pathogens but can also cause tissue damage, energetic costs, and even death through excessive cytokine and chemokine production. Because antimicrobial responses are necessary for host defense, hosts have evolved cooperative defenses to mitigate the costs of immunity. Using Yersinia pseudotuberculosis infection in mice, we demonstrate that dietary methionine supplementation protects against cytokine-mediated anorexia, wasting, blood-brain barrier dysfunction, and lethality without impairing microbial killing. Methionine and its metabolite S-adenosyl methionine (SAM) activate renal mTORC1 signaling, promoting renal growth and enhanced glomerular filtration function. This enables urinary clearance of pro-inflammatory cytokines from the circulation, limiting their systemic accumulation and the resulting sickness and lethality. This work reveals an unappreciated role for the kidneys in controlling systemic cytokine responses during infection. It also suggests that nutrient-based interventions targeting metabolic signaling can mitigate the harmful trade-offs of immune defense, offering potential therapeutic avenues to reduce infection-related costs, including death.
{"title":"Dietary methionine mitigates immune-mediated damage by enhancing renal clearance of cytokines","authors":"Katia Troha, Shrikaar Kambhampati, Arianna Insenga, Christian M. Metallo, Janelle S. Ayres","doi":"10.1016/j.cmet.2025.12.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.12.011","url":null,"abstract":"The immune system defends against pathogens but can also cause tissue damage, energetic costs, and even death through excessive cytokine and chemokine production. Because antimicrobial responses are necessary for host defense, hosts have evolved cooperative defenses to mitigate the costs of immunity. Using <em>Yersinia pseudotuberculosis</em> infection in mice, we demonstrate that dietary methionine supplementation protects against cytokine-mediated anorexia, wasting, blood-brain barrier dysfunction, and lethality without impairing microbial killing. Methionine and its metabolite <em>S</em>-adenosyl methionine (SAM) activate renal mTORC1 signaling, promoting renal growth and enhanced glomerular filtration function. This enables urinary clearance of pro-inflammatory cytokines from the circulation, limiting their systemic accumulation and the resulting sickness and lethality. This work reveals an unappreciated role for the kidneys in controlling systemic cytokine responses during infection. It also suggests that nutrient-based interventions targeting metabolic signaling can mitigate the harmful trade-offs of immune defense, offering potential therapeutic avenues to reduce infection-related costs, including death.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"264 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022167","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 : 2026-01-13DOI: 10.1016/j.cmet.2025.12.008
Jutta Jalkanen, Jiawei Zhong, Pamela A. Nono Nankam, Nayanika Bhalla, Merve Elmastas, Jiaxin Luo, Sophie Weinbrenner, Scott Frendo-Cumbo, Benedek Pesti, William Gourash, Anita Courcoulas, Zinger Yang Loureiro, Arne Dietrich, Jesper Bäckdahl, Anders Thorell, Marcus Buggert, Joanna Kalucka, Margo P. Emont, Evan D. Rosen, Matthias Blüher, Peter Kovacs, Patrik L. Ståhl, Lucas Massier, Mikael Rydén, Niklas Mejhert
{"title":"Cytoarchitectural multi-depot profiling reveals immune-metabolic crosstalk in human colon-associated adipose tissue","authors":"Jutta Jalkanen, Jiawei Zhong, Pamela A. Nono Nankam, Nayanika Bhalla, Merve Elmastas, Jiaxin Luo, Sophie Weinbrenner, Scott Frendo-Cumbo, Benedek Pesti, William Gourash, Anita Courcoulas, Zinger Yang Loureiro, Arne Dietrich, Jesper Bäckdahl, Anders Thorell, Marcus Buggert, Joanna Kalucka, Margo P. Emont, Evan D. Rosen, Matthias Blüher, Peter Kovacs, Patrik L. Ståhl, Lucas Massier, Mikael Rydén, Niklas Mejhert","doi":"10.1016/j.cmet.2025.12.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.12.008","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"30 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961688","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 : 2026-01-12DOI: 10.1016/j.cmet.2025.12.004
Thomas Marjot, Kieran Smith, Felix Westcott, Sarah White, Elspeth Johnson, Nikola Srnic, Amy Barrett, Ellis Hall, Kate Gralton, Kaitlyn Dennis, Hamish Miller, Riccardo Pofi, Jeremy F.L. Cobbold, Rebecca Richmond, Fredrik Karpe, Ronnie Blazev, Matthew J. Watt, Benjamin L. Parker, Leanne Hodson, David W. Ray, Jeremy W. Tomlinson
Hepatic lipid and glucose metabolism have been shown to be under tight circadian control in pre-clinical models. However, it remains unknown whether diurnal patterns exist in functional processes governing intrahepatic lipid accumulation in humans. We performed metabolic phenotyping, including state-of-the-art stable isotope techniques, during day and night in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and overweight controls (NCT05962099). The primary outcome was diurnal change in hepatic de novo lipogenesis (DNL), alongside a number of secondary outcomes, including changes in hepatic glucose production, glucose disposal, plasma non-esterified fatty acids (NEFAs), and whole-body glucose and lipid oxidation. We show that nighttime metabolic dysfunction is a hallmark of MASLD with multiple pathogenic pathways upregulated at night, including hepatic and peripheral insulin resistance, DNL, and systemic NEFA exposure. Insulin resistance is compounded by lower plasma insulin levels at night, secondary to reduced insulin secretion and elevated insulin clearance. Diurnal differences persist when performing identical investigations after weight loss with liver fat reductions, suggesting that nighttime metabolic dysfunction may be a primary driver of steatosis. These findings will help establish the optimal window for energy intake, exercise, and medication delivery in patients with MASLD. Integrated proteomics of plasma, adipose, and skeletal muscle tissue across day and night also identified a number of specific molecular targets that may offer therapeutic potential in the treatment of metabolic disease.
{"title":"Human MASLD is a diurnal disease driven by multisystem insulin resistance and reduced insulin availability at night","authors":"Thomas Marjot, Kieran Smith, Felix Westcott, Sarah White, Elspeth Johnson, Nikola Srnic, Amy Barrett, Ellis Hall, Kate Gralton, Kaitlyn Dennis, Hamish Miller, Riccardo Pofi, Jeremy F.L. Cobbold, Rebecca Richmond, Fredrik Karpe, Ronnie Blazev, Matthew J. Watt, Benjamin L. Parker, Leanne Hodson, David W. Ray, Jeremy W. Tomlinson","doi":"10.1016/j.cmet.2025.12.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.12.004","url":null,"abstract":"Hepatic lipid and glucose metabolism have been shown to be under tight circadian control in pre-clinical models. However, it remains unknown whether diurnal patterns exist in functional processes governing intrahepatic lipid accumulation in humans. We performed metabolic phenotyping, including state-of-the-art stable isotope techniques, during day and night in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and overweight controls (NCT05962099). The primary outcome was diurnal change in hepatic <em>de novo</em> lipogenesis (DNL), alongside a number of secondary outcomes, including changes in hepatic glucose production, glucose disposal, plasma non-esterified fatty acids (NEFAs), and whole-body glucose and lipid oxidation. We show that nighttime metabolic dysfunction is a hallmark of MASLD with multiple pathogenic pathways upregulated at night, including hepatic and peripheral insulin resistance, DNL, and systemic NEFA exposure. Insulin resistance is compounded by lower plasma insulin levels at night, secondary to reduced insulin secretion and elevated insulin clearance. Diurnal differences persist when performing identical investigations after weight loss with liver fat reductions, suggesting that nighttime metabolic dysfunction may be a primary driver of steatosis. These findings will help establish the optimal window for energy intake, exercise, and medication delivery in patients with MASLD. Integrated proteomics of plasma, adipose, and skeletal muscle tissue across day and night also identified a number of specific molecular targets that may offer therapeutic potential in the treatment of metabolic disease.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"64 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961687","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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