Pub Date : 2025-10-07DOI: 10.1016/j.cmet.2025.09.004
Yunzi Mao, Mei Cui, Yanfeng Jiang, Haowen Yu, Meng Wang, Gang Li, Haihui Zhang, Cheng Zhao, Yanxin Shen, Yupeng Hu, Yanpeng An, Yan Lin, Yiyuan Yuan, Pengcheng Lin, Xingdong Chen, Wei Xu, Shi-Min Zhao
The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer’s disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of α2, but not α1, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates α2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. α2-p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, α2-p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKα2 as a specific amino acid abundance detector for protein synthesis.
{"title":"AMPKα2 signals amino acid insufficiency to inhibit protein synthesis","authors":"Yunzi Mao, Mei Cui, Yanfeng Jiang, Haowen Yu, Meng Wang, Gang Li, Haihui Zhang, Cheng Zhao, Yanxin Shen, Yupeng Hu, Yanpeng An, Yan Lin, Yiyuan Yuan, Pengcheng Lin, Xingdong Chen, Wei Xu, Shi-Min Zhao","doi":"10.1016/j.cmet.2025.09.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.004","url":null,"abstract":"The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer’s disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of <em>α2</em>, but not <em>α1</em>, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates α2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. α2<em>-</em>p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, α2<em>-</em>p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKα2 as a specific amino acid abundance detector for protein synthesis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"128 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241311","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 : 2025-10-06DOI: 10.1016/j.cmet.2025.09.002
Martin Picard, Nirosha J. Murugan
Living organisms are physical-energetic systems that must obey simple principles guiding energy transformation across physical and temporal scales. The energy resistance principle (ERP) describes behavior and transformation of energy in the carbon-based circuitry of biology. We show how energy resistance (éR) is the fundamental property that enables transformation, converting into useful work the unformed energy potential of food-derived electrons fluxing toward oxygen. Although éR is required to sustain life, excess éR directly causes reductive and oxidative stress, heat, inflammation, molecular damage, and information loss—all hallmarks of disease and aging. We discuss how disease-causing stressors elevate éR and circulating growth differentiation factor 15 (GDF15) levels, whereas sleep, physical activity, and restorative interventions that promote healing minimize éR. The ERP is a testable general framework for discovering the modifiable bioenergetic forces that shape development, aging, and the dynamic health-disease continuum.
{"title":"The energy resistance principle","authors":"Martin Picard, Nirosha J. Murugan","doi":"10.1016/j.cmet.2025.09.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.002","url":null,"abstract":"Living organisms are physical-energetic systems that must obey simple principles guiding energy transformation across physical and temporal scales. The energy resistance principle (ERP) describes behavior and transformation of energy in the carbon-based circuitry of biology. We show how energy resistance (éR) is the fundamental property that enables transformation, converting into useful work the unformed energy potential of food-derived electrons fluxing toward oxygen. Although éR is required to sustain life, excess éR directly causes reductive and oxidative stress, heat, inflammation, molecular damage, and information loss—all hallmarks of disease and aging. We discuss how disease-causing stressors elevate éR and circulating growth differentiation factor 15 (GDF15) levels, whereas sleep, physical activity, and restorative interventions that promote healing minimize éR. The ERP is a testable general framework for discovering the modifiable bioenergetic forces that shape development, aging, and the dynamic health-disease continuum.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"68 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229362","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 : 2025-10-06DOI: 10.1016/j.cmet.2025.09.003
Xin Yin, Azhar Anwar, Linbo Yan, Ranran Yu, Yang Luo, Liang Shi, Botao Li, Jiehao Chen, Gaoli Liang, Yongci Chen, Jie Tang, Jie Liang, Yansheng Kan, Zhihao Zhang, Xiahuan Zhou, Jizheng Ma, Chenbo Ji, Yanbo Wang, Qipeng Zhang, Jing Li, Xi Chen
Paternal exercise influences exercise capacity and metabolic health of offspring, but the underlying mechanisms remain poorly understood. We demonstrate that offspring sired by exercise-trained fathers display intrinsic exercise adaptations and improved metabolic parameters compared with those sired by sedentary fathers. Similarly, offspring born to transgenic mice with muscle-specific overexpression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a booster of mitochondrial function, exhibit improved endurance capacity and metabolic traits, even in the absence of the inherited PGC-1α transgene. Injecting sperm small RNAs from exercised fathers into normal zygotes recapitulates exercise-trained phenotypes in offspring at the behavioral, metabolic, and molecular levels. Mechanistically, exercise training and muscular PGC-1α overexpression remodel sperm microRNAs, which directly suppress nuclear receptor corepressor 1 (NCoR1), a functional antagonist of PGC-1α, in early embryos, thereby reprogramming transcriptional networks to promote mitochondrial biogenesis and oxidative metabolism. Overall, this study underscores a causal role for paternal PGC-1α, sperm microRNAs, and embryonic NCoR1 in transmitting exercise-induced phenotypes and metabolic adaptations to offspring.
{"title":"Paternal exercise confers endurance capacity to offspring through sperm microRNAs","authors":"Xin Yin, Azhar Anwar, Linbo Yan, Ranran Yu, Yang Luo, Liang Shi, Botao Li, Jiehao Chen, Gaoli Liang, Yongci Chen, Jie Tang, Jie Liang, Yansheng Kan, Zhihao Zhang, Xiahuan Zhou, Jizheng Ma, Chenbo Ji, Yanbo Wang, Qipeng Zhang, Jing Li, Xi Chen","doi":"10.1016/j.cmet.2025.09.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.003","url":null,"abstract":"Paternal exercise influences exercise capacity and metabolic health of offspring, but the underlying mechanisms remain poorly understood. We demonstrate that offspring sired by exercise-trained fathers display intrinsic exercise adaptations and improved metabolic parameters compared with those sired by sedentary fathers. Similarly, offspring born to transgenic mice with muscle-specific overexpression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a booster of mitochondrial function, exhibit improved endurance capacity and metabolic traits, even in the absence of the inherited PGC-1α transgene. Injecting sperm small RNAs from exercised fathers into normal zygotes recapitulates exercise-trained phenotypes in offspring at the behavioral, metabolic, and molecular levels. Mechanistically, exercise training and muscular PGC-1α overexpression remodel sperm microRNAs, which directly suppress nuclear receptor corepressor 1 (NCoR1), a functional antagonist of PGC-1α, in early embryos, thereby reprogramming transcriptional networks to promote mitochondrial biogenesis and oxidative metabolism. Overall, this study underscores a causal role for paternal PGC-1α, sperm microRNAs, and embryonic NCoR1 in transmitting exercise-induced phenotypes and metabolic adaptations to offspring.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"16 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229363","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 : 2025-09-25DOI: 10.1016/j.cmet.2025.09.001
Ying Zhang, Weixin Liu, Chi Chun Wong, Qian Song, Xinyue Zhang, Qianying Zhou, Xuxin Ren, Xiaoxue Ren, Ruiyan Xuan, Yutong Zhao, Linfu Xu, Xiaoxing Li, Lixia Xu, Xiang Zhang, Ming Kuang, Jun Yu
The role of gut microbes in the pathogenesis of hepatocellular carcinoma (HCC) remains unclear. Here, we identified that Catenibacterium is enriched in both the feces and tumors of patients with HCC. C. mitsuokai accelerated HCC carcinogenesis in both conventional and germ-free mice. Furthermore, C. mitsuokai disrupted the gut barrier and translocated to the liver as live bacteria. Critically, the C. mitsuokai surface protein Gtr1/RagA interacts with the γ-catenin receptor on HCC cells, facilitating its attachment and colonization in the mouse liver. We further revealed that the pro-tumorigenic effect of C. mitsuokai depends on its secreted metabolite, quinolinic acid. Mechanistically, quinolinic acid binds to and activates the tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (TIE2) on HCC cells. Phosphorylated TIE2 subsequently activates the downstream oncogenic phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, thereby promoting HCC progression. In summary, C. mitsuokai disrupts the gut barrier, colonizes HCC cells via Gtr1/RagA-γ-catenin, and secretes quinolinic acid, which binds to TIE2 and drives the PI3K/AKT pathway to promote HCC development.
{"title":"Catenibacterium mitsuokai promotes hepatocellular carcinogenesis by binding to hepatocytes and generating quinolinic acid","authors":"Ying Zhang, Weixin Liu, Chi Chun Wong, Qian Song, Xinyue Zhang, Qianying Zhou, Xuxin Ren, Xiaoxue Ren, Ruiyan Xuan, Yutong Zhao, Linfu Xu, Xiaoxing Li, Lixia Xu, Xiang Zhang, Ming Kuang, Jun Yu","doi":"10.1016/j.cmet.2025.09.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.001","url":null,"abstract":"The role of gut microbes in the pathogenesis of hepatocellular carcinoma (HCC) remains unclear. Here, we identified that <em>Catenibacterium</em> is enriched in both the feces and tumors of patients with HCC. <em>C. mitsuokai</em> accelerated HCC carcinogenesis in both conventional and germ-free mice. Furthermore, <em>C. mitsuokai</em> disrupted the gut barrier and translocated to the liver as live bacteria. Critically, the <em>C. mitsuokai</em> surface protein Gtr1/RagA interacts with the γ-catenin receptor on HCC cells, facilitating its attachment and colonization in the mouse liver. We further revealed that the pro-tumorigenic effect of <em>C. mitsuokai</em> depends on its secreted metabolite, quinolinic acid. Mechanistically, quinolinic acid binds to and activates the tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (TIE2) on HCC cells. Phosphorylated TIE2 subsequently activates the downstream oncogenic phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, thereby promoting HCC progression. In summary, <em>C. mitsuokai</em> disrupts the gut barrier, colonizes HCC cells via Gtr1/RagA-γ-catenin, and secretes quinolinic acid, which binds to TIE2 and drives the PI3K/AKT pathway to promote HCC development.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"73 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134335","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 : 2025-09-24DOI: 10.1016/j.cmet.2025.08.012
Chunni Li, Yiwen Lu, Yihong Li, Ting Liu, Hong Deng, Mingchao Gao, Boxuan Zhou, Jiayu Liu, Junchao Cai, Di Huang, Linbin Yang, Jin Jin, Dongming Kuang, Shicheng Su
The incidence of certain types of extrahepatic cancers significantly increases in nonalcoholic fatty liver disease (NAFLD), the mechanisms of which are elusive. Here, we demonstrate that NAFLD is correlated with a higher risk of breast cancer in individuals with atypical hyperplasia and poor prognosis in patients with breast cancer. In mice, fatty liver exosomes are preferentially accumulated in adipocytes, and their enrichment in mammary adipocytes fosters a pro-tumor breast microenvironment. Adipocyte tropism is dictated by the binding of exosomal ErbB4 to neuregulin 4 (Nrg4). tRNA methyltransferase 10 homolog C (TRMT10C) in fatty liver exosomes translocates to mitochondria and inhibits Nd5 and Nd6 mRNA translation by inducing N1-methyladenosine modifications in adipocytes. ND5 and ND6 reduction increases reactive oxygen species and consequently enhances free fatty acid release, which fuels tumor progression. Plasma ErbB4+ exosomes are an independent prognostic factor for patients with breast cancer and comorbid NAFLD. Collectively, we reveal a liver-breast metabolic remote interaction that drives cancer development.
{"title":"Liver-breast communication of adipocyte-oriented exosomes drives primary mammary cancer progression","authors":"Chunni Li, Yiwen Lu, Yihong Li, Ting Liu, Hong Deng, Mingchao Gao, Boxuan Zhou, Jiayu Liu, Junchao Cai, Di Huang, Linbin Yang, Jin Jin, Dongming Kuang, Shicheng Su","doi":"10.1016/j.cmet.2025.08.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.012","url":null,"abstract":"The incidence of certain types of extrahepatic cancers significantly increases in nonalcoholic fatty liver disease (NAFLD), the mechanisms of which are elusive. Here, we demonstrate that NAFLD is correlated with a higher risk of breast cancer in individuals with atypical hyperplasia and poor prognosis in patients with breast cancer. In mice, fatty liver exosomes are preferentially accumulated in adipocytes, and their enrichment in mammary adipocytes fosters a pro-tumor breast microenvironment. Adipocyte tropism is dictated by the binding of exosomal ErbB4 to neuregulin 4 (Nrg4). tRNA methyltransferase 10 homolog C (TRMT10C) in fatty liver exosomes translocates to mitochondria and inhibits Nd5 and Nd6 mRNA translation by inducing <em>N</em><sup>1</sup>-methyladenosine modifications in adipocytes. ND5 and ND6 reduction increases reactive oxygen species and consequently enhances free fatty acid release, which fuels tumor progression. Plasma ErbB4<sup>+</sup> exosomes are an independent prognostic factor for patients with breast cancer and comorbid NAFLD. Collectively, we reveal a liver-breast metabolic remote interaction that drives cancer development.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"59 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127338","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 : 2025-09-23DOI: 10.1016/j.cmet.2025.08.009
Yi Xiao, Ying Xu, Han Wang, Fan Yang, Xiao-Hong Ding, Tong Fu, Li Chen, Xi Jin, Ya-Xin Zhao, Ying Wang, Fenfang Chen, Zhi-Ming Shao, Yi-Zhou Jiang
Immunotherapy demonstrates limited efficacy in triple-negative breast cancer (TNBC), influenced by intricate metabolic interactions within the tumor microenvironment. Here, we developed a single-cell RNA sequencing (scRNA-seq) immunotherapy cohort (N = 27) and a spatial transcriptomics cohort (N = 88) to elucidate metabolic crosstalk associated with therapeutic efficacy in TNBC. We illustrated that heme binding protein 2 (HEBP2)high tumor cells (featured by active glutathione metabolism) and CCL3+ macrophages (characterized by oxidative metabolism) indicated immunotherapy efficacy and were quantitatively and spatially negatively correlated. HEBP2-mediated glutamine face-off between these cell types induced this phenomenon. Mechanistically, HEBP2 disrupted FOXA1 cytoplasmic phase separation, promoting its nuclear translocation to upregulate glutathione S-transferase P1 (GSTP1) expression and glutamine consumption in tumor cells. This metabolic shift induced ferroptosis of CCL3+ macrophages, impairing the antitumor immunity. The utilization of a GSTP1 inhibitor sensitized TNBC to immunotherapy. Collectively, we delineate a tumor-macrophage metabolic checkpoint governed by the HEBP2/GSTP1 axis and pioneer single-cell-level immunometabolism as a paradigm for evaluating immunotherapeutic vulnerabilities.
{"title":"HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer","authors":"Yi Xiao, Ying Xu, Han Wang, Fan Yang, Xiao-Hong Ding, Tong Fu, Li Chen, Xi Jin, Ya-Xin Zhao, Ying Wang, Fenfang Chen, Zhi-Ming Shao, Yi-Zhou Jiang","doi":"10.1016/j.cmet.2025.08.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.009","url":null,"abstract":"Immunotherapy demonstrates limited efficacy in triple-negative breast cancer (TNBC), influenced by intricate metabolic interactions within the tumor microenvironment. Here, we developed a single-cell RNA sequencing (scRNA-seq) immunotherapy cohort (<em>N</em> = 27) and a spatial transcriptomics cohort (<em>N</em> = 88) to elucidate metabolic crosstalk associated with therapeutic efficacy in TNBC. We illustrated that heme binding protein 2 (HEBP2)<sup>high</sup> tumor cells (featured by active glutathione metabolism) and CCL3<sup>+</sup> macrophages (characterized by oxidative metabolism) indicated immunotherapy efficacy and were quantitatively and spatially negatively correlated. HEBP2-mediated glutamine face-off between these cell types induced this phenomenon. Mechanistically, HEBP2 disrupted FOXA1 cytoplasmic phase separation, promoting its nuclear translocation to upregulate glutathione S-transferase P1 (GSTP1) expression and glutamine consumption in tumor cells. This metabolic shift induced ferroptosis of CCL3<sup>+</sup> macrophages, impairing the antitumor immunity. The utilization of a GSTP1 inhibitor sensitized TNBC to immunotherapy. Collectively, we delineate a tumor-macrophage metabolic checkpoint governed by the HEBP2/GSTP1 axis and pioneer single-cell-level immunometabolism as a paradigm for evaluating immunotherapeutic vulnerabilities.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"35 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116504","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 : 2025-09-23DOI: 10.1016/j.cmet.2025.08.010
Yu Cao, Yang Zhao, Tan Deng, Qigang Zhou, Gang Hu, Zhuang-Li Hu, Yan-Yi Jiang, Xiao-Han Yang, Fang Wang, Peng-Fei Wu, Jian-Guo Chen
Extensive research highlights impaired brain energy metabolism in neuropsychiatric disorders, whereas much less is known about the role of the peripheral metabolic state. The liver is the metabolic hub, and herein we demonstrate that hepatic hydrolysis of acetyl-coenzyme A, a central metabolic intermediate, signals the brain and helps buffer stress. Using a chronic social defeat stress paradigm in male mice, we observed a hepatic glucose-to-acetate metabolic switch, followed by a glucocorticoid-repressed transcription of the acetyl-coenzyme A hydrolase, acetyl-coenzyme A thioesterase 12, to confer stress vulnerability. Hepatic overexpression of acetyl-coenzyme A thioesterase 12 alleviated depression-like phenotypes via increasing acetate output to promote histone acetylation in the ventral hippocampus, which bolstered the expression of programmed cell death ligand 1 in astrocytes, limiting neuroinflammation and rescuing inhibitory synaptic transmission dysfunction. Our findings demonstrate that hepatic acetyl-coenzyme A hydrolysis serves as a key liver-brain axis component that regulates depression susceptibility.
{"title":"Hepatic acetyl-CoA metabolism modulates neuroinflammation and depression susceptibility via acetate","authors":"Yu Cao, Yang Zhao, Tan Deng, Qigang Zhou, Gang Hu, Zhuang-Li Hu, Yan-Yi Jiang, Xiao-Han Yang, Fang Wang, Peng-Fei Wu, Jian-Guo Chen","doi":"10.1016/j.cmet.2025.08.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.010","url":null,"abstract":"Extensive research highlights impaired brain energy metabolism in neuropsychiatric disorders, whereas much less is known about the role of the peripheral metabolic state. The liver is the metabolic hub, and herein we demonstrate that hepatic hydrolysis of acetyl-coenzyme A, a central metabolic intermediate, signals the brain and helps buffer stress. Using a chronic social defeat stress paradigm in male mice, we observed a hepatic glucose-to-acetate metabolic switch, followed by a glucocorticoid-repressed transcription of the acetyl-coenzyme A hydrolase, acetyl-coenzyme A thioesterase 12, to confer stress vulnerability. Hepatic overexpression of acetyl-coenzyme A thioesterase 12 alleviated depression-like phenotypes via increasing acetate output to promote histone acetylation in the ventral hippocampus, which bolstered the expression of programmed cell death ligand 1 in astrocytes, limiting neuroinflammation and rescuing inhibitory synaptic transmission dysfunction. Our findings demonstrate that hepatic acetyl-coenzyme A hydrolysis serves as a key liver-brain axis component that regulates depression susceptibility.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"56 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116930","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 : 2025-09-18DOI: 10.1016/j.cmet.2025.08.011
Gokberk Unal, Yu-Qing Xie, Martin Fussenegger
Hypercholesterolemia is a complex metabolic disorder resulting from dysregulated lipid metabolism and is a significant risk factor for atherosclerosis, coronary artery disease, and myocardial infarction. To address the challenge of dyslipidemia, we present the cholesterol homeostasis and regulation module (CHARM), a designer genetic circuit engineered to sense elevated cholesterol levels in real time and strengthen the innate cholesterol homeostasis machinery. The circuit incorporates a custom fusion protein consisting of the Krüppel-associated box (KRAB) domain and a modified sterol regulatory element (SRE)-binding protein 1a (SREBP1a) as a sensor platform, along with a synthetic expression module containing SRE operator sites downstream of a constitutive promoter that enables the production of a therapeutic protein to reduce low-density lipoprotein cholesterol (LDL-C) levels in a closed-loop fashion. Implantation of microencapsulated CHARM-transgenic human cells in hypercholesterolemic mice rapidly restored and subsequently stably maintained cholesterol homeostasis.
{"title":"A closed-loop cholesterol shunt controlling experimental dyslipidemia","authors":"Gokberk Unal, Yu-Qing Xie, Martin Fussenegger","doi":"10.1016/j.cmet.2025.08.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.011","url":null,"abstract":"Hypercholesterolemia is a complex metabolic disorder resulting from dysregulated lipid metabolism and is a significant risk factor for atherosclerosis, coronary artery disease, and myocardial infarction. To address the challenge of dyslipidemia, we present the cholesterol homeostasis and regulation module (CHARM), a designer genetic circuit engineered to sense elevated cholesterol levels in real time and strengthen the innate cholesterol homeostasis machinery. The circuit incorporates a custom fusion protein consisting of the Krüppel-associated box (KRAB) domain and a modified sterol regulatory element (SRE)-binding protein 1a (SREBP1a) as a sensor platform, along with a synthetic expression module containing SRE operator sites downstream of a constitutive promoter that enables the production of a therapeutic protein to reduce low-density lipoprotein cholesterol (LDL-C) levels in a closed-loop fashion. Implantation of microencapsulated CHARM-transgenic human cells in hypercholesterolemic mice rapidly restored and subsequently stably maintained cholesterol homeostasis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"38 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078554","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 : 2025-09-16DOI: 10.1016/j.cmet.2025.08.008
Christina Mayerhofer, Dan Li, Trine Kristiansen, Ernst Mayerhofer, Azeem Sharda, Giulia Schiroli, Karin Gustafsson, Lingli He, Michael Mazzola, Sam Keyes, Anna Kiem, Eve Crompton, Yanxin Xu, Sovannarith Korm, Zhixun Dou, Charles Vidoudez, Peter G. Miller, Nick van Gastel, Timothy A. Graubert, David T. Scadden
Acute myeloid leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells in vivo before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDXs) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting BCAAs further reduced chemoresistant AML cells, but relapse still occurred. Among the persisting cells, we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate- and iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA. We found that OGFOD1 upregulates protein synthesis in AML, driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML while sparing normal hematopoiesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation. Targeting OGFOD1 may offer a distinctive, translation-modifying means of reducing the chemopersisting cells that drive relapse.
{"title":"OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis","authors":"Christina Mayerhofer, Dan Li, Trine Kristiansen, Ernst Mayerhofer, Azeem Sharda, Giulia Schiroli, Karin Gustafsson, Lingli He, Michael Mazzola, Sam Keyes, Anna Kiem, Eve Crompton, Yanxin Xu, Sovannarith Korm, Zhixun Dou, Charles Vidoudez, Peter G. Miller, Nick van Gastel, Timothy A. Graubert, David T. Scadden","doi":"10.1016/j.cmet.2025.08.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.008","url":null,"abstract":"Acute myeloid leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells <em>in vivo</em> before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDXs) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting BCAAs further reduced chemoresistant AML cells, but relapse still occurred. Among the persisting cells, we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate- and iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA. We found that OGFOD1 upregulates protein synthesis in AML, driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML while sparing normal hematopoiesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation. Targeting OGFOD1 may offer a distinctive, translation-modifying means of reducing the chemopersisting cells that drive relapse.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"15 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067875","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 : 2025-09-05DOI: 10.1016/j.cmet.2025.08.005
Vitor Rosetto Muñoz, Francois Moreau, Marion Soto, Yoshiyuki Watanabe, Loc-Duyen Pham, Jimmy Zhong, Sam Zimmerman, Bruna B. Brandao, Khyati Girdhar, Julian Avila, Hui Pan, Jonathan M. Dreyfuss, Michael Y. Mi, Robert E. Gerszten, Emrah Altindis, Aleksandar Kostic, Clary B. Clish, C. Ronald Kahn
Diet and obesity contribute to insulin resistance and type 2 diabetes, in part via the gut microbiome. To explore the role of gut-derived metabolites in this process, we assessed portal/peripheral blood metabolites in mice with different risks of obesity/diabetes, challenged with a high-fat diet (HFD) + antibiotics. In diabetes/obesity-prone C57BL/6J mice, 111 metabolites were portally enriched and 74 were peripherally enriched, many of which differed in metabolic-syndrome-resistant 129S1/129S6 mice. Vancomycin treatment of HFD-fed C57BL/6J mice modified the microbiome and the portal/peripheral ratio of many metabolites, including upregulating tricarboxylic acid (TCA) cycle-related metabolites, like mesaconate, in portal blood. Treatment of isolated hepatocytes with mesaconate, itaconate, or citraconate improved insulin signaling and transcriptionally regulated genes involved in gluconeogenesis, fatty acid oxidation, and lipogenesis in vitro and in vivo. In humans, citraconate levels are inversely correlated with plasma glucose. Thus, portal versus peripheral metabolites play important roles in mediating effects of the microbiome on hepatic metabolism and the pathogenesis of HFD-related insulin resistance.
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