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}
Cell metabolismPub Date : 2025-06-16DOI: 10.1016/j.cmet.2025.05.011
Christy M. Gliniak, Ruth Gordillo, Yun-Hee Youm, Qian Lin, Clair Crewe, Zhuzhen Zhang, Bianca C. Field, Teppei Fujikawa, Megan Virostek, Shangang Zhao, Yi Zhu, Clifford J. Rosen, Tamas L. Horvath, Vishwa Deep Dixit, Philipp E. Scherer
{"title":"FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression","authors":"Christy M. Gliniak, Ruth Gordillo, Yun-Hee Youm, Qian Lin, Clair Crewe, Zhuzhen Zhang, Bianca C. Field, Teppei Fujikawa, Megan Virostek, Shangang Zhao, Yi Zhu, Clifford J. Rosen, Tamas L. Horvath, Vishwa Deep Dixit, Philipp E. Scherer","doi":"10.1016/j.cmet.2025.05.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.05.011","url":null,"abstract":"Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence of adiponectin, a hormone known to regulate ceramide breakdown. These results suggest that fat tissue is a central site for FGF21’s beneficial effects and point to its potential for treating metabolic syndrome and age-related diseases by promoting a healthier metabolic profile under dietary stress and extending healthspan and lifespan.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"13 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296296","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 : 2025-06-16DOI: 10.1016/j.cmet.2025.05.012
Mengtian Shan, Song Zhang, Zhibing Luo, Shengjie Deng, Linyu Ran, Quan Zhou, Huimin Wan, Jihui Ye, Chenchen Qian, Ximin Fan, Yun Feng, David W. Morse, Joerg Herrmann, Qiang Li, Zhongliang Guo, Feilong Wang
{"title":"Itaconate promotes inflammatory responses in tissue-resident alveolar macrophages and exacerbates acute lung injury","authors":"Mengtian Shan, Song Zhang, Zhibing Luo, Shengjie Deng, Linyu Ran, Quan Zhou, Huimin Wan, Jihui Ye, Chenchen Qian, Ximin Fan, Yun Feng, David W. Morse, Joerg Herrmann, Qiang Li, Zhongliang Guo, Feilong Wang","doi":"10.1016/j.cmet.2025.05.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.05.012","url":null,"abstract":"Itaconate is an anti-inflammatory metabolite with therapeutic potential in multiple inflammatory diseases. However, its immunomodulatory function has been mainly based on <em>ex vivo</em>-generated macrophages or cell lines, whereas its role in tissue-resident macrophages is still poorly understood. Here, we report that, in contrast to its effects on bone-marrow-derived macrophages (BMDMs), itaconate promotes the production of proinflammatory cytokines and augments the activation of the NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome in resident alveolar macrophages (AMs). Unlike native itaconate, the itaconate derivatives dimethyl itaconate (DI) and 4-octyl itaconate (4OI) suppress the inflammatory response in AMs. Notably, the intratracheal transfer of BMDMs reversed their responsiveness to itaconate, indicating an essential role of the alveolar microenvironment in shaping macrophage immunometabolism. We also demonstrate that itaconate promotes AM-mediated inflammatory responses <em>in vivo</em> and aggravates lung injury. Taken together, our study unexpectedly demonstrates a proinflammatory role of itaconate in tissue-resident AMs, suggesting that further investigations are needed before its clinical application.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"10 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296297","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 : 2025-06-12DOI: 10.1016/j.cmet.2025.05.010
Jesse S.S. Novak, Lisa Polak, Sanjeethan C. Baksh, Douglas W. Barrows, Marina Schernthanner, Benjamin T. Jackson, Elizabeth A.N. Thompson, Anita Gola, M. Deniz Abdusselamoglu, Alain R. Bonny, Kevin A.U. Gonzales, Julia S. Brunner, Anna E. Bridgeman, Katie S. Stewart, Lynette Hidalgo, June Dela Cruz-Racelis, Ji-Dung Luo, Shiri Gur-Cohen, H. Amalia Pasolli, Thomas S. Carroll, Elaine Fuchs
{"title":"The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury","authors":"Jesse S.S. Novak, Lisa Polak, Sanjeethan C. Baksh, Douglas W. Barrows, Marina Schernthanner, Benjamin T. Jackson, Elizabeth A.N. Thompson, Anita Gola, M. Deniz Abdusselamoglu, Alain R. Bonny, Kevin A.U. Gonzales, Julia S. Brunner, Anna E. Bridgeman, Katie S. Stewart, Lynette Hidalgo, June Dela Cruz-Racelis, Ji-Dung Luo, Shiri Gur-Cohen, H. Amalia Pasolli, Thomas S. Carroll, Elaine Fuchs","doi":"10.1016/j.cmet.2025.05.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.05.010","url":null,"abstract":"Epidermal stem cells produce the skin’s barrier that excludes pathogens and prevents dehydration. Hair follicle stem cells (HFSCs) are dedicated to bursts of hair regeneration, but upon injury, they can also reconstruct, and thereafter maintain, the overlying epidermis. How HFSCs balance these fate choices to restore physiologic function to damaged tissue remains poorly understood. Here, we uncover serine as an unconventional, non-essential amino acid that impacts this process. When dietary serine dips, endogenous biosynthesis in HFSCs fails to meet demands (and vice versa), slowing hair cycle entry. Serine deprivation also alters wound repair, further delaying hair regeneration while accelerating re-epithelialization kinetics. Mechanistically, we show that HFSCs sense each fitness challenge by triggering the integrated stress response, which acts as a rheostat of epidermal-HF identity. As stress levels rise, skin barrier restoration kinetics accelerate while hair growth is delayed. Our findings offer potential for dietary and pharmacological intervention to accelerate wound healing.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"589 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269254","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}
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