Nature Cell Biology最新文献

{"title":"The glycolytic enzyme PGAM1 functions as a metabolic–autophagy checkpoint to coordinate growth and stress tolerance","authors":"Yi Zhang, Pengwei Zhao, Hangfei Liang, Zhaojie Liu, Shuling Dong, Yingcong Chen, Weijing Yao, Yuting Chen, Liting Yang, Zhonglan Shi, Lei Zhang, Yibin Pan, Fanghong Zheng, Qi Lin, Shichao Wang, Jinheng Pan, Mingzhu Fan, Shan Feng, Cheng Ma, Lifeng Pan, Ying Xing, Fan Yang, Shuiping Liu, Du Feng, Qiming Sun, Guixin Zhu, Cong Yi","doi":"10.1038/s41556-026-02034-3","DOIUrl":"10.1038/s41556-026-02034-3","url":null,"abstract":"Cell survival requires tight coordination between growth-promoting metabolism and cellular quality-control pathways, yet how these processes are integrated remains unclear. Here we identify the conserved glycolytic enzyme PGAM1 as a metabolic-autophagy checkpoint that links glycolysis to autophagy initiation independently of its catalytic activity. Using complementary yeast and mammalian systems we show that PGAM1 functions as a molecular scaffold that recruits phosphatidylinositol 3-kinase complex I to the phagophore assembly site, thereby licensing autophagosome biogenesis. This autophagy-regulatory function is genetically essential, evolutionarily conserved and functionally separable from glycolysis. It is regulated by Atg1/ULK1-mediated phosphorylation that enhances Atg14 binding under starvation. Functionally, PGAM1 coordinates anabolic growth and stress-induced survival to maintain cellular homeostasis. In cancer, PGAM1 upregulation enhances both glycolytic flux and autophagy capacity. Disruption of either function markedly impairs tumour growth, establishing PGAM1 as a homeostatic checkpoint that is hijacked in cancer to drive both proliferation and stress tolerance. Zhang, Zhao, Liang et al. report that, independent of its catalytic function, the glycolytic enzyme PGAM1 acts as a scaffold protein to regulate autophagy activation, thereby modulating cellular homeostasis and stress response.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 9","pages":"1830-1845"},"PeriodicalIF":22.7,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148612787","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":"Nuclear class 3 PI3K co-activates fasting-specific chromatin remodelling","authors":"Nathaniel F. Henneman, Genki Kawamura, Ying Luo, Catia Oliveira Dias, Jiaqi Su, Arianna Segaloni, Ivan Nemazanyy, Samuel le Cam, Calvin Rodrigues, Nicolas Kuperwasser, Nicolas Cagnard, Karim Hnia, Raphaël Margueron, Dominik Lutter, Takeaki Ozawa, Ganna Panasyuk","doi":"10.1038/s41556-026-02030-7","DOIUrl":"10.1038/s41556-026-02030-7","url":null,"abstract":"Transcriptional remodelling during fasting ensures metabolic adaptation and provides health benefits across species. Although several regulators of fasting-induced transcription and chromatin are known, how nutrient levels directly influence RNA polymerase II (RNAPII) and epigenetic writers remains unclear. Here we show that lipid kinase class 3 phosphatidylinositol 3-kinase (PI3K-3), a master regulator of autophagy, also functions on chromatin as a co-activator of epigenetic writers to promote RNAPII transcription. PI3K-3 overlaps with transcriptionally engaged RNAPII phosphorylated at Ser5 and with Setd1a/COMPASS, the complex that deposits the activating H3K4me3 mark. Nuclear PI3K-3 interacts with RNAPII and Setd1a/COMPASS and promotes their chromatin binding. PI3K-3 loss reduces RNAPII-S5p and H3K4me3 at selected genes, whereas PI3K-3 overexpression co-activates p300/CBP and chromatin-targeted PI3K-3 increases H3K4me3. During starvation, PI3K-3 induces autophagy genes and drives fasted liver towards ketogenesis and lipid degradation. These findings link nutrient stress to chromatin-mediated transcriptional activation. Henneman et al. report an unexpected role for class 3 PI3K (PI3K-3) acting as a transcriptional co-activator during fasting. They show that nuclear PI3K-3 co-activates the methyltransferase Set1/COMPASS complex to promote H3K4me3 deposition.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 9","pages":"1875-1889"},"PeriodicalIF":22.7,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-02030-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer stem cells are hyper-responsive sensors of the tumour microenvironment and regulate metastasis dynamics through YAP/TAZ","authors":"Binwu Tang, Jacob Minin, Victoria M. Gonzalez, Zoya Z. Khan, Andrew R. Gaines, Yuval Raviv, Yu-an Yang, Christine P. Carney, Zachary G. Millman, Daniel Grun, Cristiana M. Pineda, Alina Sharma, Dominic Esposito, Hualong Yan, Jing Huang, Andy D. Tran, Michael Kruhlak, Howard H. Yang, Maxwell P. Lee, Lalage M. Wakefield","doi":"10.1038/s41556-026-02013-8","DOIUrl":"10.1038/s41556-026-02013-8","url":null,"abstract":"Cancer stem cells (CSCs) drive metastasis and therapy resistance, yet their behaviour within the complex tumour microenvironment remains poorly understood. Here we use a fluorescent reporter that marks CSCs to show that CSCs and their more differentiated progeny display strikingly different population dynamics during metastatic lung colonization in breast cancer models. CSC expansion is rapidly curtailed early in colonization, suggesting a strong negative feedback mechanism acting selectively on this subpopulation. We showed that CSCs are exceptionally sensitive to local microenvironmental cues such as cell crowding and nutrient availability. They respond earlier and more extensively than their differentiated progeny, thereby coupling tumour growth to resource and space availability. Microenvironmental signals converge on the transcriptional regulatory complex YAP/TAZ/TEAD, with CSC sensitivity arising from elevated signal reception and greater chromatin accessibility at TEAD-regulated enhancers. Targeting upstream inputs to this pathway reversed chemotherapy-induced CSC enrichment in lung metastases, suggesting a potential therapeutic strategy. Using a dynamic fluorescent reporter, Tang et al. demonstrate that cancer stem cells are hyper-responsive to microenvironmental cues, which they sense and adapt to through YAP/TAZ signalling, thereby playing an essential role in breast cancer lung metastasis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 8","pages":"1728-1741"},"PeriodicalIF":22.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-02013-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Every scientist has a role in advocacy","authors":"Veronica J. Farmer, Amy S. Gladfelter","doi":"10.1038/s41556-026-02012-9","DOIUrl":"10.1038/s41556-026-02012-9","url":null,"abstract":"In this Comment, we call on scientists to share their stories. Through casual conversation or prepared presentations, with images or essays, scientists can advocate for their research and reach taxpayers and elected officials at a time when science funding and public trust are undermined, particularly in the USA.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 8","pages":"1596-1598"},"PeriodicalIF":22.7,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148585032","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":"Mapping mesenchymal diversity in the human small intestine and organoids","authors":"Kelli F. Johnson, Xiangning Dong, Yu-Hwai Tsai, Angeline Wu, Sydney G. Clark, Abigail Vallie, Sha Huang, Charlie J. Childs, Rachel K. Zwick, Ian Glass, Katherine D. Walton, Ophir D. Klein, Jason R. Spence","doi":"10.1038/s41556-026-02027-2","DOIUrl":"10.1038/s41556-026-02027-2","url":null,"abstract":"The organization of diverse mesenchymal populations during human small intestinal development is critical for tissue architecture and function yet remains poorly defined. Here, to construct a comprehensive, tissue-scale map of the developing human small intestine at single cell resolution, we leveraged single-cell RNA-sequencing data to build a Xenium spatial transcriptomics gene panel covering the cell diversity of the human small intestine. We defined five subpopulations occupying discrete anatomical locations within the lamina propria and submucosa—the subepithelial cells, lamina propria fibroblasts, submucosal fibroblasts, smooth muscle cells and CXCL13+ fibroblasts. Our data establish molecular markers to distinguish these populations in both sequencing and imaging data. We leverage this high-resolution atlas to interrogate cell–cell signalling, benchmark pluripotent stem cell-derived human intestinal organoids and to demonstrate how this resource can incorporate relative spatial organization into tissue analysis, with broad implications for modelling development, regeneration and disease. Johnson et al. combine single-cell and spatial transcriptomics approaches to build a spatially resolved atlas of the developing human intestine and intestinal organoids, uncovering spatial organization and fibroblast heterogeneity.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 8","pages":"1758-1770"},"PeriodicalIF":22.7,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-026-02027-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148552562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes","authors":"Yuanchun Luo, Jianglong Yu, Zhuofan Li, Wanning Li, Le Jiang, Chen Huang, Zhouyi Rong, Long Lin, Yueguang Rong, Chaojun Yan, Zhishui Chen, Jingfeng Tang, He He, Anbing Shi, Zhiyin Song","doi":"10.1038/s41556-026-02010-x","DOIUrl":"10.1038/s41556-026-02010-x","url":null,"abstract":"Lysosomes are central degradative organelles essential for cellular homeostasis, yet the mechanisms that maintain their integrity and function under stress remain incompletely understood. Here we identify a previously unrecognized lysosomal renewal process, termed budding-type fission (B-fission), which restores lysosomal function during hypoxia–reoxygenation stress. During B-fission, damaged lysosomes generate membrane buds that undergo scission to form small, fully functional lysosomes, independently of autophagic lysosome reformation. Mechanistically, mitochondrial-derived vesicles (MDVs) deliver the fission adaptor MFF to lysosomes, where MFF recruits the dynamin-related GTPase DRP1 to drive membrane scission. MIRO2 promotes the formation of MFF+ MDVs through direct interaction with MFF, while the lysosomal membrane protein ITM2C binds MIRO2 to tether and guide MFF+ MDVs to lysosomes, enabling efficient MFF delivery and subsequent B-fission. Notably, AMPK activation by 991 or metformin promotes MFF-dependent lysosomal B-fission under normoxic conditions, whereas AMPK inhibition by dorsomorphin suppresses B-fission during hypoxia–reoxygenation. This stress-responsive ITM2C–MIRO2–MFF–DRP1 axis co-opts the mitochondrial division machinery to drive lysosomal fission from damaged lysosomes, thereby enabling the undamaged components to reorganize into daughter lysosomes and promote lysosomal renewal. Thus, our findings uncover a fundamental mode of lysosomal renewal and reveal an unexpected role for MDV-mediated mitochondria–lysosome communication in mediating lysosomal quality control during ischaemia–reperfusion and related stresses. Luo et al. describe a budding type of lysosome fission linked to delivery of MFF from mitochondrial-derived vesicles to lysosomes. MFF recruits DRP1 for membrane scission. This axis restores lysosome function during hypoxia–reoxygenation stress.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 8","pages":"1686-1699"},"PeriodicalIF":22.7,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148522131","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":"Borrowed scissors for lysosome fission","authors":"Shawn M. Ferguson","doi":"10.1038/s41556-026-02028-1","DOIUrl":"10.1038/s41556-026-02028-1","url":null,"abstract":"Mitochondria communicate extensively with the rest of the cell via metabolic and signalling pathways, but usually not as much by vesicle trafficking. A recent study expands this view by proposing that mitochondrial-derived vesicles deliver machinery that drives lysosome fission as part of a lysosome quality control process.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 8","pages":"1608-1609"},"PeriodicalIF":22.7,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536258","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":"Lysosomes and lysosomal dysfunction in ageing biology","authors":"Matthew L. Steinhauser, Yuan Liu, Stacey J. Sukoff Rizzo, Bill B. Chen, Toren Finkel, Jay Xiaojun Tan","doi":"10.1038/s41556-026-02007-6","DOIUrl":"10.1038/s41556-026-02007-6","url":null,"abstract":"Lysosomes are essential regulators of cellular homeostasis. Emerging evidence positions lysosomes as both vulnerable targets and active drivers of ageing biology. During ageing, lysosomes exhibit impaired biogenesis, defective acidification, reduced hydrolytic activity and compromised membrane integrity. These defects impair the clearance of damaged organelles and macromolecules and promote cellular stress responses, inflammageing and senescence, causing age-dependent functional decline across tissues. Lysosomal dysfunction has been increasingly linked to age-related diseases, including neurodegeneration, cardiometabolic disorders and increased susceptibility to infection, among others. Thus, lysosomal dysfunction is a hallmark of ageing that drives age-related pathology. Here we review recent progress in lysosomal biogenesis and quality control, discuss how lysosomes intersect with fundamental ageing mechanisms and evaluate emerging therapeutic strategies that target lysosomes to promote healthy ageing and potentially ameliorate age-associated pathologies. This Review presents lysosomal dysfunction as a hallmark of ageing that drives age-related pathology, and highlights emerging therapeutic strategies that enhance lysosomal activity to promote healthy ageing or ameliorate ageing-related diseases.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 8","pages":"1626-1639"},"PeriodicalIF":22.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148451767","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":"Single-cell transcriptomics uncovers endothelial progenitor-like remodelling driving human coronary atherosclerosis progression","authors":"Fang Yao, Fangzhou Li, Shujie Gai, Yinan Chen, Fei Liu, Xingzhong Zhang, Jun Li, Lin Mao, Liliang Guo, Kun Xing, Juan Huang, Shufang Fu, Yang Sun, Jinhua Chen, Heng Zhang, Yihan Chen, Bingying Zhou, Li Wang, Zhe Zheng","doi":"10.1038/s41556-026-02022-7","DOIUrl":"10.1038/s41556-026-02022-7","url":null,"abstract":"Coronary atherosclerosis underlies life-threatening conditions such as myocardial infarction and stroke, yet its cellular dynamics remain incompletely understood. Here, through single-cell RNA sequencing of 27,941 cells from 56 human coronary segments, we constructed a disease-stage-resolved cellular atlas, revealing pathological remodelling of endothelial cells (ECs) into a progenitor-like state (EC5SLCO4A1+) with low expression of canonical EC dysfunction signatures. EC5SLCO4A1+ abundance increased with atherosclerotic stage, and its emergence is driven by PRDM15 through direct transcriptional activation. Analysis of the EC5SLCO4A1+ interaction network revealed extensive crosstalk with immune cell types, the interaction between which contributed to atherosclerotic progression. Endothelial overexpression of Prdm15 in vivo exacerbated atherosclerosis, while its suppression ameliorated the disease phenotype, with diminished EC5SLCO4A1+-like cells and immune infiltration. Our findings underscore the central role of EC subtype remodelling in the progression of human coronary atherosclerosis and reveal tractable targets for therapeutic intervention. Yao, Li, Gai et al. profile normal coronary artery and early and advanced coronary atherosclerosis samples from humans using single-cell transcriptomics and identify a progenitor-like endothelial subtype with functional implications in disease progression","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 8","pages":"1671-1685"},"PeriodicalIF":22.7,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432457","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":"Neuroproteasomes in tau pathology","authors":"Melina Casadio","doi":"10.1038/s41556-026-02015-6","DOIUrl":"10.1038/s41556-026-02015-6","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 7","pages":"1346-1346"},"PeriodicalIF":22.7,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432126","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}