Cell metabolismPub Date : 2025-07-17DOI: 10.1016/j.cmet.2025.06.011
Tiezhu Shi, Jialiang Shao, Yufeng Ding, Hong Tang, Xiangyin Tan, Sisi Zhou, Shaoqing Yu, Xiang Wang, Guanzhen Yu, Ninghan Feng, Xiongjun Wang
{"title":"Xylulose 5-phosphate fosters sustained antitumor activity of progenitor-like exhausted SLC35E2+ CD8+ T effector cells","authors":"Tiezhu Shi, Jialiang Shao, Yufeng Ding, Hong Tang, Xiangyin Tan, Sisi Zhou, Shaoqing Yu, Xiang Wang, Guanzhen Yu, Ninghan Feng, Xiongjun Wang","doi":"10.1016/j.cmet.2025.06.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.011","url":null,"abstract":"Metabolic adaptations involved in tumor metastasis and immune evasion merit investigation. Here, using <em>in vivo</em> metabolic CRISPR/Cas9 knockout screening, we identified xylulokinase (XYLB) as a tumor suppressor that impairs lung colonialization by producing xylulose 5-phosphate (Xu5P), which promotes CD8<sup>+</sup> T cell cytotoxicity. Mechanistically, CD8<sup>+</sup> T cells express relatively high levels of solute carrier family 35 member E2 (SLC35E2), a homolog of the plant Xu5P transporter, to facilitate Xu5P uptake and subsequently intensify the pentose phosphate pathway and glycolysis for energy/redox balance. Furthermore, we revealed that Xu5P potentiates CD8<sup>+</sup> T cell response by promoting Xu5P-responsive progenitor-like SLC35E2<sup>+</sup> CD8<sup>+</sup> exhausted T cells via tet methylcytosine dioxygenase 3 (TET3)-mediated DNA demethylation of the <em>Tcf7</em> promoter. Clinically, elevated XYLB or blood Xu5P correlates with enhanced CD8<sup>+</sup> T cell efficacy and reduced metastasis. In murine models, Xu5P supplementation or adopting Xu5P-rich diets synergizes with anti-PD-1 therapy to enhance antitumor immunity. These findings offer insights into the potentiality of dietary interventions for metastatic cancer.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"14 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645740","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}
Cell metabolismPub Date : 2025-07-16DOI: 10.1016/j.cmet.2025.06.010
Lauralyne Dumont, Gabriel Richard, Romain Espagnet, Frédérique Frisch, Mélanie Fortin, Arnaud Samson, Jonathan Bouchard, Réjean Fontaine, Etienne Croteau, Serge Phoenix, Stéphanie Dubreuil, Brigitte Guérin, Éric E. Turcotte, André C. Carpentier, Denis P. Blondin
{"title":"Shivering, but not adipose tissue thermogenesis, increases as a function of mean skin temperature in cold-exposed men and women","authors":"Lauralyne Dumont, Gabriel Richard, Romain Espagnet, Frédérique Frisch, Mélanie Fortin, Arnaud Samson, Jonathan Bouchard, Réjean Fontaine, Etienne Croteau, Serge Phoenix, Stéphanie Dubreuil, Brigitte Guérin, Éric E. Turcotte, André C. Carpentier, Denis P. Blondin","doi":"10.1016/j.cmet.2025.06.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.010","url":null,"abstract":"Skin cooling results in the activation of heat-generating mechanisms to counteract heat lost to the environment. Here, we aim to understand the extent to which variations in cold-stimulated heat production may be driven by differences in the contribution of shivering and non-shivering thermogenesis (NST) and the interaction with biological sex. Using a novel mean skin temperature clamping technique in healthy men and women, our data show that cold-stimulated heat production rises with increasing shivering and myocardial oxidative metabolism in a skin temperature-dependent fashion. Shivering and myocardial thermogenesis were also moderately associated. By contrast, adipose tissue NST did not increase in a linear manner to reductions in skin temperature. Men and women displayed similar thermoregulatory responses, although women presented more pronounced shivering through a greater recruitment of lower-body muscles and a greater number of motor units recruited. Thus, shivering contributes proportionally to cold-induced thermogenesis, whereas adipose tissue thermogenesis displays an all-or-none response.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"16 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640632","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}
Cell metabolismPub Date : 2025-07-14DOI: 10.1016/j.cmet.2025.06.009
Jason C.L. Tong, Charlotte Frazer-Morris, Ali H. Shilleh, Katrina Viloria, Anne de Bray, Adithya Muraleedaran Nair, Paul R.V. Johnson, Rebecca Spiers, Ahmad Kobiita, Oladapo E. Olaniru, Shanta J. Persaud, Robert Hauffe, André Kleinridders, Carsten Schultz, C. Bruce Verchere, Canqi Cui, Jonathan E. Campbell, Malgorzata Cyranka, Alexey Epanchintsev, Carina Ämmälä, David J. Hodson
{"title":"Localized GLP1 receptor pre-internalization directs pancreatic alpha cell to beta cell communication","authors":"Jason C.L. Tong, Charlotte Frazer-Morris, Ali H. Shilleh, Katrina Viloria, Anne de Bray, Adithya Muraleedaran Nair, Paul R.V. Johnson, Rebecca Spiers, Ahmad Kobiita, Oladapo E. Olaniru, Shanta J. Persaud, Robert Hauffe, André Kleinridders, Carsten Schultz, C. Bruce Verchere, Canqi Cui, Jonathan E. Campbell, Malgorzata Cyranka, Alexey Epanchintsev, Carina Ämmälä, David J. Hodson","doi":"10.1016/j.cmet.2025.06.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.009","url":null,"abstract":"Pancreatic alpha cells modulate beta cell function in a paracrine manner through the release of glucagon. However, the detailed molecular architecture underlying alpha-to-beta cell regulation remains poorly characterized. Here, we show that the glucagon-like peptide-1 receptor (GLP1R) is enriched as nanodomains on beta cell membranes that contact alpha cells, in keeping with increased single-molecule transcript expression. At low glucose, beta cells next to alpha cells directly sense micromolar glucagon release by pre-internalizing GLP1R. Pre-internalized GLP1R is associated with earlier beta cell Ca<sup>2+</sup> responses to high glucose, which are then propagated across the islet. Beta cells adjacent to alpha cells are more secretory than beta cells next to other beta cells. Localized GLP1R signaling occurs <em>in vitro</em> and <em>in vivo</em>, is operative in the post-prandial state, and GLP1R contacts decrease between beta cells and alpha cells during metabolic stress. Thus, we detail a regulated pathway through which glucagon modulates insulin release.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"29 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622478","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}
Cell metabolismPub Date : 2025-07-02DOI: 10.1016/j.cmet.2025.06.002
Ruize Qu, Yi Zhang, Bora Kim, Guangyi Zeng, Pengcheng Wang, Weike Shaoyong, Ying Huang, Wanwan Guo, Yang Chen, Ping Wang, Qing Yang, Siyi Lu, Xin Zhou, Jing Weng, Jinkun Xu, Jun Lin, Kai Wang, Yanpeng Ma, Shogo Takahashi, Yuhong Luo, Lulu Sun
{"title":"Microbial riboflavin inhibits ceramide synthase 3 to lower ceramide (d18:1/26:0) and delay colorectal cancer progression","authors":"Ruize Qu, Yi Zhang, Bora Kim, Guangyi Zeng, Pengcheng Wang, Weike Shaoyong, Ying Huang, Wanwan Guo, Yang Chen, Ping Wang, Qing Yang, Siyi Lu, Xin Zhou, Jing Weng, Jinkun Xu, Jun Lin, Kai Wang, Yanpeng Ma, Shogo Takahashi, Yuhong Luo, Lulu Sun","doi":"10.1016/j.cmet.2025.06.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.002","url":null,"abstract":"Ceramide metabolism dysregulation links to colorectal cancer (CRC) progression, yet the mechanism remains unknown. d18:1/26:0 ceramide (C26) levels were elevated in patients with CRC and mouse models, which activated epidermal growth factor receptor (EGFR) by binding its extracellular region to promote cancer cell proliferation. The rise of C26 levels was mainly driven by heightened ceramide synthase 3 (CERS3) activity. High CERS3 expression generally accelerated tumor progression, yet some patients exhibited significant heterogeneity, suggesting endogenous metabolites available to affect CERS3 activity. We found that the abundance of <em>Bacteroides cellulosilyticus</em> affects tumor heterogeneity by producing riboflavin that inhibits CERS3 activity, thus delaying CRC progression. Moreover, aclidinium bromide, an FDA-approved drug, exhibited significant inhibitory effects on CERS3 activity, suggesting its potential application in CRC treatment. These findings elucidate the metabolic pathways and mechanisms underlying ceramide’s impact on CRC, highlighting that targeting CERS3 inhibition represents a promising therapeutic strategy for CRC.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"50 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533897","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}
Cell metabolismPub Date : 2025-07-01DOI: 10.1016/j.cmet.2025.06.001
David W. Frederick, Joseph P. McGaunn, Joseph A. Baur
{"title":"Muscle needs NAD, but how much?","authors":"David W. Frederick, Joseph P. McGaunn, Joseph A. Baur","doi":"10.1016/j.cmet.2025.06.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.001","url":null,"abstract":"Supplements that increase nicotinamide adenine dinucleotide (NAD) have become increasingly popular, and much of the attention has focused on potential benefits to skeletal muscle. In this issue of <em>Cell Metabolism</em>, Chubanava et al.<span><span><sup>1</sup></span></span> use an inducible model to lower NAD concentration in the muscles of adult mice, revealing a surprising lack of functional consequences.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"10 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520776","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}
Cell metabolismPub Date : 2025-07-01DOI: 10.1016/j.cmet.2025.06.003
Charles Brenner
{"title":"The NARly side of whole-body NAD homeostasis","authors":"Charles Brenner","doi":"10.1016/j.cmet.2025.06.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.06.003","url":null,"abstract":"Nicotinic acid riboside (NAR), one of two nucleoside precursors of nicotinamide adenine dinucleotide (NAD) coenzymes, is revealed to function in systemic NAD homeostasis. By knocking out <em>Nmnat1</em> in liver, investigators discovered a liver-to-kidney NAR transit pathway and learned that kidney can be a donor in addition to a receiver of NAD precursors.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"46 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521195","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":"RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation","authors":"Zezhao Chen, Xiaosong Gu, Hongbo Chen, Huijing Zhang, Jianping Liu, Xiaohua Yang, Yuping Cai, Mengmeng Zhang, Lingjie Yan, Yuanxin Yang, Bing Shan, Zheng-Jiang Zhu, Yixiao Zhang, Jinyang Gu, Daichao Xu","doi":"10.1016/j.cmet.2025.05.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.05.014","url":null,"abstract":"The capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient sensing in metabolic pathways is well understood, the mechanisms linking nutrient signals to cell death remain unclear. Here, we show that RIPK1, a key mediator of cell death and inflammation, senses methionine and its metabolite, <em>S</em>-adenosylmethionine (SAM), to dictate cell survival and death. SAM-mediated symmetrical dimethylation at RIPK1 Arg606 by PRMT5 functions as a physiological protective brake against RIPK1 activation. Metabolic perturbations, such as methionine restriction or disrupted one-carbon flux, reduce SAM levels and unmask Arg606, promoting RIPK1 self-association and <em>trans</em>-activation, thereby triggering apoptosis and inflammation. Thus, RIPK1 is a physiological SAM sensor linking methionine and one-carbon metabolism to the control of life-or-death decisions. Our findings suggest that RIPK1 could be a potential target for diseases associated with disrupted SAM availability.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"141 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479512","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":"Sphingomyelins in mosquito saliva reconfigure skin lipidome to promote viral protein levels and enhance transmission of flaviviruses","authors":"Hacène Medkour, Lauryne Pruvost, Elliott F. Miot, Xiaoqian Gong, Virginie Vaissayre, Mihra Tavadia, Pascal Boutinaud, Justine Revel, Atitaya Hitakarun, Wannapa Sornjai, Jim Zoladek, R. Duncan Smith, Sébastien Nisole, Esther Nolte-‘t Hoen, Justine Bertrand-Michel, Dorothée Missé, Guillaume Marti, Julien Pompon","doi":"10.1016/j.cmet.2025.05.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.05.015","url":null,"abstract":"Many flaviviruses with high pandemic potential are transmitted through mosquito bites. While mosquito saliva is essential for transmission and represents a promising pan-flaviviral target, there is a dearth of knowledge on salivary metabolic transmission enhancers. Here, we show that extracellular vesicle (EV)-derived sphingomyelins in mosquito saliva reconfigure the human cell lipidome to increase viral protein levels, boosting skin infection and enhancing transmission for flaviviruses. Lipids within internalized mosquito EVs enhance infection in fibroblast and immune human primary cells for multiple flaviviruses. Mosquito EV lipids selectively increase viral translation by inhibiting infection-induced endoplasmic reticulum (ER)-associated degradation of viral proteins. Infection enhancement solely results from the sphingomyelins within salivary mosquito EVs that augment human cell sphingomyelin concentration. Finally, EV-lipid co-inoculation exacerbates disease severity <em>in vivo</em> in mouse transmission assays. By discovering and elucidating how metabolic components of mosquito saliva promote transmission of flaviviruses, our study unveils lipids as a new category of targets against vectored transmission.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"14 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329130","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}
Cell metabolismPub Date : 2025-06-19DOI: 10.1016/j.cmet.2025.05.013
Xiaohui Zhang, Zhongliang Nie, Shuang Wang, Yuxi Ma, Dan Han, Ting Hu, Liu Liu, Liying Men, Tao Zhang, Xiaoting Wu, Xu Li, Sheng Hu, Meng Yuan, Liu Liu, Chaoqun Wang, Ping Xu, Limin Xiang, Jiao Liu, Yong Zhang, Dahai Zhu, Wei Yan
{"title":"Arachidonic acid triggers spermidine synthase secretion from primary tumor to induce skeletal muscle weakness upon irradiation","authors":"Xiaohui Zhang, Zhongliang Nie, Shuang Wang, Yuxi Ma, Dan Han, Ting Hu, Liu Liu, Liying Men, Tao Zhang, Xiaoting Wu, Xu Li, Sheng Hu, Meng Yuan, Liu Liu, Chaoqun Wang, Ping Xu, Limin Xiang, Jiao Liu, Yong Zhang, Dahai Zhu, Wei Yan","doi":"10.1016/j.cmet.2025.05.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.05.013","url":null,"abstract":"Radiotherapy reduces the risk of cancer recurrence and death, but the fact that it's accompanied by multiple side effects including muscle fibrosis and weakness, seriously affects the life quality of patients. However, the underlying mechanism is poorly defined. Here, we identify that cancer cells secrete more spermidine synthase (SRM) enzyme through small extracellular vesicles to trigger skeletal muscle weakness upon radiotherapy. Mechanistically, irradiation-triggered arachidonic acid (ArA) accumulation elevates the ISGylation of the SRM protein, facilitating SRM packaging into extracellular vesicles from the primary tumor. Circulating SRM results in spermidine accumulation in skeletal muscle and type I collagen fiber biosynthesis in an eIF5A-dependent manner. However, losartan treatment blocks the ISGylation of SRM and its subsequent secretion. Collectively, our findings determine that ArA functions in concert for circulating SRM secretion upon radiotherapy, which aggravates skeletal muscle fibrosis through rewiring polyamine metabolism, shedding light on the alleviation of radiotherapy-mediated muscle weakness when combined with losartan treatment.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"25 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319499","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}