Nature metabolism最新文献

{"title":"Increasing cytosolic NADPH to mimic exercise","authors":"Bryce J. Carpenter, Pieterjan Dierickx","doi":"10.1038/s42255-026-01580-2","DOIUrl":"10.1038/s42255-026-01580-2","url":null,"abstract":"In this issue of Nature Metabolism, Wu et al. reveal that cytosolic NADPH, a pentose phosphate pathway metabolite, drives a physiological cardiac hypertrophic response that is protective against heart attack injury and can be raised by a candidate spermidine derivative.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 9","pages":"1827-1828"},"PeriodicalIF":27.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia–reperfusion injury in the heart","authors":"Dan Wu, Tao Chen, Xin Dong, Haoqi Li, Zijie Cheng, Huimin Li, Yufan Chao, Fangling Li, Yun Yin, Fujun Guo, Xinran Xu, Yuxuan Zhang, Kun Ning, Xiaoqing Fu, Yuemin Bian, Fenfen Ma, Julia Ritterhoff, Wang Wang, Qingxun Hu","doi":"10.1038/s42255-026-01587-9","DOIUrl":"10.1038/s42255-026-01587-9","url":null,"abstract":"Exercise promotes physiological cardiomyocyte growth and protects against ischaemia–reperfusion (IR) injury in the heart. The molecular mechanism by which exercise benefits cardiac metabolism and function remains largely unknown. Here, using a genetically encoded fluorescent sensor, we show that exercise increases cytosolic, but not mitochondrial, NADPH levels in cardiomyocytes. This effect is mediated by activation of the pentose phosphate pathway (PPP). Inhibition of PPP activity or depletion of cytosolic NADPH attenuates exercise-induced heart hypertrophy in mice. We observe that NADPH promotes cardiomyocyte growth by inhibiting HDAC3/C/EBPβ pathways. Moreover, exercise-activated PPP/NADPH pathway suppresses acute IR injury and preserves heart function 4 weeks after IR. Among 310 tested Tibetan compounds, the spermidine derivative lyciumspermidine-0527 directly activates the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase, elevates intracellular NADPH levels and alleviates IR injury. Altogether, these results show that PPP-derived NADPH is a critical metabolic checkpoint that regulates exercise-induced physiological cardiomyocyte growth and protects against IR-induced heart injury. NADPH derived from the pentose phosphate pathway is shown to mediate exercise-induced physiological cardiac hypertrophy and protect against damage caused by ischaemia–reperfusion injury.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 9","pages":"1888-1909"},"PeriodicalIF":27.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASS1-derived argininosuccinate promotes purine nucleoside synthesis in B cell acute lymphoblastic leukaemia","authors":"Gen Li, Zhijun He, Mingjie Liu, Junhua Zhao, Haichuan Zhu, Cefan Zhou, Zhenning Wang, Xiaojing He, Jingfeng Tang, Peng Jiang","doi":"10.1038/s42255-026-01586-w","DOIUrl":"10.1038/s42255-026-01586-w","url":null,"abstract":"Metabolic remodelling underlies tumour progression. However, how metabolites act as signalling molecules to support cancer cell proliferation remains unclear. Here we show that argininosuccinate (ASA), a key intermediate of the urea cycle, promotes purine nucleoside biosynthesis in tyrosine kinase-driven haematological malignancies. Mechanistically, BCR–ABL phosphorylates argininosuccinate synthase 1 (ASS1), which increases ASA production from citrulline. ASA directly binds cytosolic 5′-nucleotidase II (NT5C2) and enhances its nucleosidase activity. The resulting purine nucleosides serve as a carbon source for glycolysis and the tricarboxylic acid cycle, which supports leukaemia cell proliferation under glucose-replete conditions. Loss of ASS1 or NT5C2 disrupts central carbon metabolism and inhibits leukaemia progression in vivo, which can be rescued with inosine or adenosine supplementation. Collectively, our findings uncover an ASA–NT5C2 signalling axis linking urea cycle dysregulation to purine metabolism, and identify purine nucleosides as a carbon source in tyrosine kinase-driven haematological malignancies. Argininosuccinate produced by phosphorylated ASS1 allosterically enhances the nucleosidase activity of NT5C2, resulting in increased production of purine nucleosides, which serve as a carbon source in BCR–Abl-positive haematological cancers.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 9","pages":"1871-1887"},"PeriodicalIF":27.5,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148899541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Combined alcohol and cannabinoid exposure leads to synergistic toxicity by affecting cerebellar Purkinje cells","authors":"Guichang Zou, Jing Xia, Heyi Luo, Dan Xiao, Jin Jin, Chenjian Miao, Xin Zuo, Qianqian Gao, Zhi Zhang, Tian Xue, Yezi You, Ye Zhang, Li Zhang, Wei Xiong","doi":"10.1038/s42255-026-01602-z","DOIUrl":"10.1038/s42255-026-01602-z","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 9","pages":"2035-2035"},"PeriodicalIF":27.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01602-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota-derived imidazole propionate promotes primary sclerosing cholangitis via p38 signalling","authors":"Antonio Molinaro, Peder Rustøen Braadland, Guido Carpino, Alba Carreras, Marios Nikolaidis, Petra Hanzely, Katharina R. Beck, Ahmad H. Ali, Lars Bossen, Anna Frank, Annika Lundqvist, Brian D. Juran, Diletta Overi, Lei Geng, Enya Amundsen‑Isaksen, Henrik Mikael Reims, Ida Björk, Krzysztof Grzyb, Andreas Abildgaard, Trine Folseraas, Martin Cornillet, Hólmfríður Helgadóttir, Bryan M. McCauley, Laura Cristoferi, Marco Carbone, Vincenzo Cardinale, Marte L. Høivik, Lise Katrine Engesæter, Sara K. V. Tjønnfjord, Adrian McCann, Per M. Ueland, Mette Vesterhus, Tom H. Karlsen, Henning Grønbæk, Eugenio Gaudio, Konstantinos N. Lazaridis, Annika Bergquist, Espen Melum, Fredrik Bäckhed, Johannes Roksund Hov","doi":"10.1038/s42255-026-01600-1","DOIUrl":"10.1038/s42255-026-01600-1","url":null,"abstract":"Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts that can lead to biliary cancer and end-stage liver disease. PSC is associated with inflammatory bowel disease and an altered gut microbiota. However, the molecular mechanisms underlying gut–liver interactions in PSC remain poorly characterized. Here we show that the gut microbiota-derived metabolite imidazole propionate (ImP) is a disease driver in PSC. Individuals with PSC have higher circulating ImP levels than individuals with related conditions, and high ImP levels predict reduced survival in PSC. Cholangiocytes exposed to ImP show activated mammalian target of rapamycin complex 1 (mTORC1) signalling and secrete pro-inflammatory and pro-fibrogenic factors. Chronic administration of ImP to mice induces liver inflammation and fibrosis through a p38-dependent mechanism, upstream of mTORC1. We propose that chronic exposure to ImP induces cholangiocyte injury, which alone or in concert with other factors causes clinical worsening of PSC. Therefore, targeting ImP production or signalling may represent therapeutic avenues in PSC. The gut microbial metabolite imidazole propionate (ImP) is shown to promote primary sclerosing cholangitis (PSC) in mice. In humans with PSC, circulating ImP levels are elevated and correlated with poor survival.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 9","pages":"1910-1925"},"PeriodicalIF":27.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01600-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UBE2N flips the switch on for mitophagy and off for MASH","authors":"Emily D. Madigan, Sandro L. Matos, Michael J. Jurczak","doi":"10.1038/s42255-026-01604-x","DOIUrl":"10.1038/s42255-026-01604-x","url":null,"abstract":"Mitochondrial homeostasis is tightly regulated to prevent hepatocyte injury. In this issue of Nature Metabolism, Wang et al. identify UBE2N as a switch that determines whether hepatocytes undergo protective mitophagy or pathogenic cell death in metabolic dysfunction-associated steatohepatitis (MASH).","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 9","pages":"1-3"},"PeriodicalIF":27.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Impaired cAMP–PKA–CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia","authors":"Elia Angelino, Lorenza Bodo, Roberta Sartori, Valeria Malacarne, Beatrice D’Anna, Nicolò Formaggio, Suvham Barua, Tommaso Raiteri, Andrea Lauria, Simone Reano, Alessandra Murabito, Monica Nicolau, Fabiana Ferrero, Camilla Pezzini, Giulia Rossino, Francesco Favero, Michele Valmasoni, Nicoletta Filigheddu, Alessio Menga, Davide Corà, Emilio Hirsch, Salvatore Oliviero, Vittorio Sartorelli, Valentina Proserpio, Alessandra Ghigo, Marco Sandri, Paolo E. Porporato, Daniela Talarico, Giuseppina Caretti, Andrea Graziani","doi":"10.1038/s42255-026-01622-9","DOIUrl":"10.1038/s42255-026-01622-9","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 9","pages":"1-1"},"PeriodicalIF":27.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-026-01622-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis","authors":"Feng Wang, Jin Lee, Jeong-Su Park, Meizhou Huang, Hwan Ma, Guoyan Sui, Zixiong Zhou, Michitaka Matsuda, So Yeon Kim, Takashi Tsuchiya, Xuefeng Wu, Haram Lee, Soohwan Oh, Hanseul Park, Key-Hwan Lim, Chun-Woong Park, Sang-Bae Han, Jin Tae Hong, Michael Karin, Yoon Seok Roh, Ekihiro Seki","doi":"10.1038/s42255-026-01590-0","DOIUrl":"10.1038/s42255-026-01590-0","url":null,"abstract":"K63-linked ubiquitination (K63) is closely associated with the interaction, intracellular trafficking or activity of tagged proteins. However, its role during metabolic dysfunction-associated steatohepatitis (MASH) is largely unknown. Here we show that UBE2N, a ubiquitin-conjugating enzyme that specializes in creating K63, is downregulated by THAP11 in human and mouse hepatocytes with MASH. While hepatocyte-specific Ube2n deficiency exacerbates western diet-induced MASH and fibrosis via PANoptosis and impaired mitophagy, its overexpression reverses these pathological phenotypes and restores hepatic homeostasis. Mechanistically, UBE2N increases PARKIN-mediated K63-p62 at lysine 420, promoting K63-p62 translocation into damaged mitochondria for mitophagic clearance. Ube2n deficiency, conversely, induces cytoplasmic p62 accumulation and NRF2 hyperactivation, driving PANoptosis. Additional Sqstm1 deletion mitigates Ube2n deletion-induced pathologies, highlighting the importance of p62 accumulation for MASH progression. Thus, our results demonstrate that hepatocyte UBE2N is essential for regulation of metabolic stress-mediated mitophagy and PANoptosis, and that p62 is a proof-of-concept target for treating MASH and fibrosis. Hepatocyte UBE2N regulates K63-linked ubiquitination of p62 to modulate mitophagy and PANoptosis in the context of MASH and fibrosis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 9","pages":"1-22"},"PeriodicalIF":27.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Publisher Correction: Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes.","authors":"Jones K Ofori, Sabrina Ruhrmann, Axel Lindström, Alexander Perfilyev, Melina Martin, Alexandros Karagiannopoulos, Lucia Scisciola, Katja Kost, Josefine Jönsson, Åsa Nilsson, Boris Kantor, Monika Dudenhöffer-Pfeifer, Marianne G Rots, Anna Wendt, Tina Rönn, Lena Eliasson, Karl Bacos, Charlotte Ling","doi":"10.1038/s42255-026-01610-z","DOIUrl":"https://doi.org/10.1038/s42255-026-01610-z","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment.","authors":"Nannan Xu, Yemin Zhu, Yichao Han, Qi Liu, Lingfeng Tong, Yakui Li, Zhangbing Chen, Sijia Shao, Wenrui He, Mingrui Li, Yi Wang, Siyuan Qiang, Peiwei Chai, Peng Du, Wenyi Zhao, Lifang Wu, Ping Zhang, Jianli He, Hecheng Li, Jinke Cheng, Renbing Jia, Bin Li, Ying Lu, Xuemei Tong","doi":"10.1038/s42255-026-01608-7","DOIUrl":"https://doi.org/10.1038/s42255-026-01608-7","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":27.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}