Nature metabolism最新文献

{"title":"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/s42255-025-01347-1","DOIUrl":"10.1038/s42255-025-01347-1","url":null,"abstract":"In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (Treg) immunosuppressive function and restraining CD8+ T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both Treg and CD8+ T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient Treg cells, loss of MondoA enhanced CD8+ T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA–TXNIP axis, which impaired TCR/CD28-signal-induced CD8+ T cell activation. Importantly, targeting the MondoA–TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA–TXNIP axis is a promising therapeutic target for improving cancer immunotherapy. Xu et al. identify the MondoA–TXNIP signalling axis as a regulator of antitumour immune surveillance in response to lactic acid in the tumour microenvironment.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1889-1904"},"PeriodicalIF":20.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900203","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":"Investigating metabolic changes in single embryos during early development in Drosophila","authors":"","doi":"10.1038/s42255-025-01375-x","DOIUrl":"https://doi.org/10.1038/s42255-025-01375-x","url":null,"abstract":"Metabolism is dynamic during early development in animals. To study this process, we developed a single-embryo metabolomics and transcriptomics method that captures rapid, small-scale changes in metabolism and how they coordinate with gene expression. Our work showcasing this method in Drosophila embryos provides a valuable resource for understanding developmental systems biology.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"192 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900305","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":"Lighting up targets of dual agonist therapies for diabetes and obesity","authors":"","doi":"10.1038/s42255-025-01346-2","DOIUrl":"10.1038/s42255-025-01346-2","url":null,"abstract":"Dual incretin agonists, such as tirzepatide (a GLP1R–GIPR agonist), show excellent efficacy for type 2 diabetes and obesity therapy. Research identifies the cells and neurons in the pancreas and brain that are targeted by dual agonists, providing further details on their modes of action.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1507-1508"},"PeriodicalIF":20.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883259","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":"Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain","authors":"Anne de Bray, Anna G. Roberts, Sarah Armour, Jason Tong, Christiane Huhn, Blaise Gatin-Fraudet, Kilian Roßmann, Ali H. Shilleh, Wanqing Jiang, Natalie S. Figueredo Burgos, James P. P. Trott, Katrina Viloria, Daniela Nasteska, Abigail Pearce, Satsuki Miyazaki, Jeremy W. Tomlinson, Dylan M. Owen, Daniel J. Nieves, Julia Ast, Malgorzata Cyranka, Alexey Epanchintsev, Carina Ämmälä, Frank Reimann, Tolga Soykan, Graham Ladds, Alice E. Adriaenssens, Stefan Trapp, Ben Jones, Johannes Broichhagen, David J. Hodson","doi":"10.1038/s42255-025-01342-6","DOIUrl":"10.1038/s42255-025-01342-6","url":null,"abstract":"Dual agonists targeting glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are breakthrough treatments for patients with type 2 diabetes and obesity. Compared to GLP1R agonists, dual agonists show superior efficacy for glucose lowering and weight reduction. However, delineation of dual agonist cell targets remains challenging. Here, we develop and test daLUXendin and daLUXendin+, non-lipidated and lipidated fluorescent GLP1R/GIPR dual agonist probes, and use them to visualize cellular targets. daLUXendins are potent GLP1R/GIPR dual agonists that advantageously show less functional selectivity for mouse GLP1R over mouse GIPR. daLUXendins label rodent and human pancreatic islet cells, with a signal intensity of β cells > α cells = δ cells. Systemic administration of daLUXendin strongly labels GLP1R+ and GIPR+ neurons in circumventricular organs characterized by an incomplete blood–brain barrier but does not penetrate the brain beyond labelling seen with single (ant)agonists. At the single-molecule level, daLUXendin targets endogenous GLP1R–GIPR nanodomains, which differ in organization and composition from those targeted by a single agonist. daLUXendins reveal dual agonist targets in the pancreas and brain and exclude a role for brain penetration in determining the superior efficacy of dual agonists, shedding new light on different modes of action of dual agonists versus single agonists. A series of fluorescent probes is designed that act as dual agonists on both GLP1 and GIP receptors, and are used to image receptor binding activities in tissues and animals.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1536-1549"},"PeriodicalIF":20.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883258","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":"Metabolic Messenger: growth differentiation factor 15","authors":"Samuel N. Breit, Vicky W. Tsai","doi":"10.1038/s42255-025-01353-3","DOIUrl":"10.1038/s42255-025-01353-3","url":null,"abstract":"Growth differentiation factor 15 (GDF15; also known as macrophage-inhibitory cytokine-1) is a stress-responsive cytokine that is overexpressed under a broad range of conditions. It has a role in regulating appetite and body weight and is an aetiological factor in anorexia–cachexia syndromes, as well as nausea and vomiting during pregnancy. Long after its original cloning, its receptor was identified as GFRAL, a distant member of the GDNF receptor family within the TGFβ superfamily, with RET as its co-receptor. Both of these are highly localized to specific hindbrain regions. Although many of GFRAL’s metabolic changes may be linked to its effect on suppressing appetite, recent findings suggest that GDF15 also independently regulates energy expenditure and insulin sensitivity. Here, we review recent literature and provide updates on the current understanding of GDF15 biology and its therapeutic applications in health and metabolic diseases. Breit and Tsai provide a concise overview of the role of GDF15 as a signalling molecule in the context of metabolic health and disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1732-1744"},"PeriodicalIF":20.8,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874235","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":"Species-specific serine metabolism differentially controls natural killer cell functions","authors":"Joey H. Li, Qinyan Feng, Andréa B. Ball, Cassidy D. Lee, Michelle L. Wallerius, Jan G. Bormin, Edmund D. Kapelczak, Wesley R. Armstrong, Leen Hermans, Abigail Krall, Nedas Matulionis, Tara TeSlaa, Heather R. Christofk, Ajit S. Divakaruni, Timothy E. O’Sullivan","doi":"10.1038/s42255-025-01348-0","DOIUrl":"10.1038/s42255-025-01348-0","url":null,"abstract":"Immune cells undergo rapid metabolic reprogramming to fuel effector responses. However, whether the metabolic pathways that supply these functions differ between human and mouse immune cells is poorly understood. Using a comparative metabolomics approach, here we show both conserved and species-distinct metabolite alterations in cytokine-activated primary human and mouse natural killer (NK) cells. Activated human NK cells fail to perform de novo serine synthesis, resulting in broadly impaired effector functions when serine starved ex vivo or during in vivo dietary serine restriction, limiting their antitumour function. In contrast, activated mouse NK cells perform de novo serine synthesis to fuel one-carbon metabolism and proliferation, resulting in increased metabolic flexibility during ex vivo and dietary serine restriction. While NK cells from both species require one-carbon metabolism to proliferate and produce interferon-γ, GCLC-dependent glutathione synthesis tunes cytotoxic versus inflammatory function in human NK cells. Thus, activated NK cell functions display species-specific requirements for serine metabolism, and environmental serine availability dictates activated human NK cell functions. Li et al. characterize overlapping and divergent metabolic requirements of human and murine NK cells in response to activation, with a focus on serine metabolism","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1905-1923"},"PeriodicalIF":20.8,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840298","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":"Resolving early embryonic metabolism in Drosophila through single-embryo metabolomics and transcriptomics","authors":"J. Eduardo Pérez-Mojica, Zachary B. Madaj, Christine Isaguirre, Joe Roy, Kin H. Lau, Ryan D. Sheldon, Adelheid Lempradl","doi":"10.1038/s42255-025-01351-5","DOIUrl":"https://doi.org/10.1038/s42255-025-01351-5","url":null,"abstract":"<p>Early embryonic development marks a shift from maternal factor reliance to zygotic control. Although transcriptional regulation during this period is well characterized, concurrent metabolic events remain largely unknown. Progress has been limited by technical challenges in analysing the small amounts of material and the rapid progression of development. Here, we present a high-resolution, single-embryo multi-omics dataset that captures transcriptional and metabolic dynamics during the first 3 h of <i>Drosophila</i> development. By profiling individual embryos, we uncover stage-specific transcriptional and metabolic programmes, including previously unrecognized transitions in nucleotides, amino acids and other metabolites. Integration of metabolites and transcript modules reveals a limited, selective functional coupling between metabolism and gene expression. This work reframes the maternal-to-zygotic transition as both a transcriptional and metabolic handoff and provides a valuable framework for studying metabolic regulation during development and beyond.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"31 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825107","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":"d-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1","authors":"Joséphine Zangari,&nbsp;Oliver Stehling,&nbsp;Sven A. Freibert,&nbsp;Kaushik Bhattacharya,&nbsp;Florian Rouaud,&nbsp;Veronique Serre-Beinier,&nbsp;Kinsey Maundrell,&nbsp;Sylvie Montessuit,&nbsp;Sabrina Myriam Ferre,&nbsp;Evangelia Vartholomaiou,&nbsp;Vinzent Schulz,&nbsp;Karim Zuhra,&nbsp;Víctor González-Ruiz,&nbsp;Sahra Hanschke,&nbsp;Takashi Tsukamoto,&nbsp;Michaël Cerezo,&nbsp;Csaba Szabo,&nbsp;Serge Rudaz,&nbsp;Michal T. Boniecki,&nbsp;Miroslaw Cygler,&nbsp;Roland Lill,&nbsp;Jean-Claude Martinou","doi":"10.1038/s42255-025-01339-1","DOIUrl":"10.1038/s42255-025-01339-1","url":null,"abstract":"Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98, an l-cystine transport system that strengthens antioxidant defences, thereby promoting tumour survival and progression. Here, we show that the d-enantiomer of cysteine (d-Cys) is selectively imported into xCT/CD98-overexpressing cancer cell lines and impairs their proliferation, particularly under high oxygen concentrations. Intracellular d-Cys specifically inhibits the mitochondrial cysteine desulfurase NFS1, a key enzyme of cellular iron–sulfur protein biogenesis, by blocking sulfur mobilization due to steric constraints. NFS1 inhibition by d-Cys affects all cellular iron–sulfur cluster-dependent functions, including mitochondrial respiration, nucleotide metabolism and maintenance of genome integrity, leading to decreased oxygen consumption, DNA damage and cell cycle arrest. d-Cys administration diminishes tumour growth of human triple-negative breast cancer cells implanted orthotopically into the mouse mammary gland. Hence, d-Cys could represent a simple therapy to selectively target those forms of cancer characterized by overexpression of xCT/CD98. Zangari et al. show that d-cysteine targets NFS1, thus affecting Fe–S cluster biogenesis and impairing tumour growth.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 8","pages":"1646-1662"},"PeriodicalIF":20.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01339-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819131","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":"The insulin signalling network","authors":"James G. Burchfield,&nbsp;Alexis Diaz-Vegas,&nbsp;David E. James","doi":"10.1038/s42255-025-01349-z","DOIUrl":"10.1038/s42255-025-01349-z","url":null,"abstract":"Insulin signalling is a central regulator of metabolism, orchestrating nutrient homeostasis and coordinating carbohydrate, protein and lipid metabolism. This network operates through dynamic, tightly regulated protein phosphorylation events involving key kinases such as AKT, shaping cellular responses with remarkable precision. Advances in phosphoproteomics have expanded our understanding of insulin signalling, revealing its intricate regulation and links to disease, particularly cardiometabolic disease. Major insights, such as the mechanisms of AKT activation and the influence of genetic and environmental factors, have emerged from studying this network. In this Review, we examine the architecture of insulin signalling, focusing on its precise temporal regulation. We highlight AKT’s central role in insulin action and its vast substrate repertoire, which governs diverse cellular functions. Additionally, we explore feedback and crosstalk mechanisms, such as insulin receptor substrate protein signalling, which integrates inputs through phosphorylation at hundreds of distinct sites. Crucially, phosphoproteomics has uncovered complexities in insulin-resistant states, where network rewiring is characterized by disrupted phosphorylation and the emergence of novel sites that are absent in healthy cells. These insights redefine insulin signalling and its dysfunction, highlighting new therapeutic opportunities. In this Review, the authors provide a detailed overview of insulin signalling and its dysfunction, highlighting new therapeutic opportunities.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1745-1764"},"PeriodicalIF":20.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819132","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":"Unlocking spatial metabolomics with isotopically labelled internal standards","authors":"","doi":"10.1038/s42255-025-01341-7","DOIUrl":"10.1038/s42255-025-01341-7","url":null,"abstract":"We present a cost-effective normalization strategy for spatial metabolomics using uniformly 13C-labelled yeast extract, which addresses limitations of conventional methods and the physico-chemical complexity of water-soluble metabolites. Our approach outperforms standard normalization strategies and reveals hitherto unrecognized metabolic remodelling in the cortex after stroke, demonstrating its applicability.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1730-1731"},"PeriodicalIF":20.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778572","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}