Postnatal depression (PND) is associated with offspring neurodevelopmental impairments, but the mechanisms remain unclear. Here, we identify an intergenerational pathway whereby maternal psychological state is encoded in breastmilk microRNAs (miRNAs) and transmitted to offspring via small extracellular vesicles (sEVs). Using cross-fostering models, we show that maternal depression disrupts newborn neuron maturation in the offspring hippocampal dentate gyrus (DG), causing cognitive deficits and depressive-like behaviors. Gastric administration of PND-derived breastmilk sEVs to healthy pups recapitulates these phenotypes. Mechanistically, PND-induced miRNAs are packaged into breastmilk sEVs and delivered to the offspring brain, where they suppress mGluR8 in supramammillary nucleus (SuM) neurons projecting to DG. This presynaptic mGluR8 deficiency drives a “high-frequency, low-amplitude” neuronal activation pattern. Inhibiting mammary sEV secretion or sequestering these miRNAs in offspring SuM neurons rescues the deficits. Our findings define a mechanism underlying PND-related offspring neurodevelopmental impairments and suggest a therapeutic target for interrupting the intergenerational transmission of maternal mental disorders.
{"title":"Postnatal depression-associated breastmilk extracellular vesicles mediate intergenerational effects on offspring neurodevelopment","authors":"Zexu Wei,Ranran Yu,Junnan Xu,Chenyu Tao,Aixia Zhang,Longjie Li,Xiaoshan Zhang,Jin He,Jiajun Yu,Xuhuang Xiao,Jiahui Guo,Tong Wang,Wei Gong,Yanbo Wang,Chen-Yu Zhang,Dijun Chen,Zhang-Peng Chen,Chenbo Ji,Xi Chen","doi":"10.1016/j.cmet.2026.09.023","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.09.023","url":null,"abstract":"Postnatal depression (PND) is associated with offspring neurodevelopmental impairments, but the mechanisms remain unclear. Here, we identify an intergenerational pathway whereby maternal psychological state is encoded in breastmilk microRNAs (miRNAs) and transmitted to offspring via small extracellular vesicles (sEVs). Using cross-fostering models, we show that maternal depression disrupts newborn neuron maturation in the offspring hippocampal dentate gyrus (DG), causing cognitive deficits and depressive-like behaviors. Gastric administration of PND-derived breastmilk sEVs to healthy pups recapitulates these phenotypes. Mechanistically, PND-induced miRNAs are packaged into breastmilk sEVs and delivered to the offspring brain, where they suppress mGluR8 in supramammillary nucleus (SuM) neurons projecting to DG. This presynaptic mGluR8 deficiency drives a “high-frequency, low-amplitude” neuronal activation pattern. Inhibiting mammary sEV secretion or sequestering these miRNAs in offspring SuM neurons rescues the deficits. Our findings define a mechanism underlying PND-related offspring neurodevelopmental impairments and suggest a therapeutic target for interrupting the intergenerational transmission of maternal mental disorders.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"5 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149250870","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}
Pub Date : 2026-10-27DOI: 10.1016/j.cmet.2026.09.022
Yun Li,Si-Tong Liu,Zi-Jing Li,Yun-Wei Du,Huai-Qiang Ju
The tumor-associated microenvironment, shaped by dynamic crosstalk between tumor cells and peritumoral adipose tissue (PAT), has attracted growing attention in recent years. Beyond serving as a passive energy reservoir, PAT actively contributes to tumor progression through metabolic reprogramming, modulation of immune cell function, and remodeling of the stromal vascular fraction. Conversely, tumors induce profound structural and functional reorganization in PAT, including fibrosis, browning, and systemic effects such as cachexia, which further enhances tumor progression. Together, these changes reinforce a tumor-supportive microenvironment. Collectively, these reciprocal interactions underscore the pivotal role of adipose tissue in shaping tumor behavior. This review provides a comprehensive overview of the multifaceted roles of PAT in tumor development, elucidates the mechanisms underlying the bidirectional tumor-adipose interaction, and discusses emerging therapeutic strategies targeting the adipose-tumor axis as a promising avenue for cancer treatment.
{"title":"Peritumoral adipose tissue: A bidirectional regulator of cancer","authors":"Yun Li,Si-Tong Liu,Zi-Jing Li,Yun-Wei Du,Huai-Qiang Ju","doi":"10.1016/j.cmet.2026.09.022","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.09.022","url":null,"abstract":"The tumor-associated microenvironment, shaped by dynamic crosstalk between tumor cells and peritumoral adipose tissue (PAT), has attracted growing attention in recent years. Beyond serving as a passive energy reservoir, PAT actively contributes to tumor progression through metabolic reprogramming, modulation of immune cell function, and remodeling of the stromal vascular fraction. Conversely, tumors induce profound structural and functional reorganization in PAT, including fibrosis, browning, and systemic effects such as cachexia, which further enhances tumor progression. Together, these changes reinforce a tumor-supportive microenvironment. Collectively, these reciprocal interactions underscore the pivotal role of adipose tissue in shaping tumor behavior. This review provides a comprehensive overview of the multifaceted roles of PAT in tumor development, elucidates the mechanisms underlying the bidirectional tumor-adipose interaction, and discusses emerging therapeutic strategies targeting the adipose-tumor axis as a promising avenue for cancer treatment.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"34 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149250869","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}
Bile acids represent one of nature’s most chemically diverse and therapeutically important metabolite families. However, the human bile acid metabolome remains largely uncharted, with analytical limitations obscuring potentially thousands of biologically active species present in cells and biofluids. Here, we present MetLLM, a transformer-based language model that learns bile acid modification patterns to prioritize candidate bile acid analogs, and MetSpace, an in silico bile acid chemical landscape containing 3,900 prioritized candidates. Liquid chromatography-high resolution mass spectrometry analysis of human feces confirmed multiple newly detected and structurally novel bile acids, including MS2141 and MS1281. In vitro functional validation showed that MS2141 modulates M2 receptor-associated Gi/o signaling and alters electrophysiological parameters in human induced pluripotent stem cell-derived cardiomyocytes. This work expands the searchable bile acid metabolome and provides a computational framework for systematic metabolite discovery.
{"title":"AI-guided discovery and expansion of the human bile acid landscape","authors":"Tianbiao Yang,Changliang Yao,Junliang Kuang,Lu Wang,Aihua Zhao,Dan Zheng,Yuanyuan Chen,Lu Liu,Qingpeng Zhang,Tianlu Chen,Ke Lan,Zhanguo Wang,Jeremy K. Nicholson,Weijia Zheng,Aiping Lyu,George Pak-Heng Leung,Wei Jia","doi":"10.1016/j.cmet.2026.09.024","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.09.024","url":null,"abstract":"Bile acids represent one of nature’s most chemically diverse and therapeutically important metabolite families. However, the human bile acid metabolome remains largely uncharted, with analytical limitations obscuring potentially thousands of biologically active species present in cells and biofluids. Here, we present MetLLM, a transformer-based language model that learns bile acid modification patterns to prioritize candidate bile acid analogs, and MetSpace, an in silico bile acid chemical landscape containing 3,900 prioritized candidates. Liquid chromatography-high resolution mass spectrometry analysis of human feces confirmed multiple newly detected and structurally novel bile acids, including MS2141 and MS1281. In vitro functional validation showed that MS2141 modulates M2 receptor-associated Gi/o signaling and alters electrophysiological parameters in human induced pluripotent stem cell-derived cardiomyocytes. This work expands the searchable bile acid metabolome and provides a computational framework for systematic metabolite discovery.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"4 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149250871","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}
This phase 2 trial included 211 Chinese participants with type 2 diabetes mellitus (mean age 48.4 years; 131 participants were male). Participants received once-weekly subcutaneous UBT251 (2 mg, 4 mg [initial dose 0.5 mg], 4 mg [initial dose 1 mg], or 6 mg), 1 mg semaglutide, or placebo for 24 weeks. At week 24, UBT251 achieved least-squares mean changes in glycated hemoglobin of −2.16% (95% CI, −2.39 to −1.92) to −1.98% (95% CI, −2.31 to −1.64), versus −1.77% (95% CI, −1.99 to −1.54) for semaglutide and −0.66% (95% CI, −0.90 to −0.41) for placebo (placebo-adjusted differences: −1.50% to −1.32%; all p < 0.001). UBT251 significantly reduced fasting blood glucose, 2-h postprandial glucose, and waist circumference versus placebo (all p < 0.001). Weight reduction with UBT251 was significantly greater than both placebo and semaglutide (all p < 0.05). Gastrointestinal events were the most common treatment-emergent adverse events. These findings support further phase 3 evaluation of UBT251. Registration: CTR20250029; NCT07163624.
{"title":"UBT251, a novel triple GLP-1, GIP, and glucagon receptor agonist, in adults with type 2 diabetes: A multicenter, randomized phase 2 trial","authors":"Zhiguang Zhou,Xiaoxia Shi,Suyuan Jiang,Sihong Wang,Hongyan Shu,Wenli Sun,Haifang Wang,Li Cong,Li Mao,Liujun Fu,Shenglian Gan,Lili Zhang,Jie Han,Yunming Gao,Wei Wang,Lei Zhang,Fang Wang,Chuqing Cao,Xiang Yan,Haiyan Zhang,Tao Su,Wei Ling,Lasse Hjort Kyneb Jakobsen,Nicolas Belmar Nazal,Huiru Yan","doi":"10.1016/j.cmet.2026.10.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.10.010","url":null,"abstract":"This phase 2 trial included 211 Chinese participants with type 2 diabetes mellitus (mean age 48.4 years; 131 participants were male). Participants received once-weekly subcutaneous UBT251 (2 mg, 4 mg [initial dose 0.5 mg], 4 mg [initial dose 1 mg], or 6 mg), 1 mg semaglutide, or placebo for 24 weeks. At week 24, UBT251 achieved least-squares mean changes in glycated hemoglobin of −2.16% (95% CI, −2.39 to −1.92) to −1.98% (95% CI, −2.31 to −1.64), versus −1.77% (95% CI, −1.99 to −1.54) for semaglutide and −0.66% (95% CI, −0.90 to −0.41) for placebo (placebo-adjusted differences: −1.50% to −1.32%; all p < 0.001). UBT251 significantly reduced fasting blood glucose, 2-h postprandial glucose, and waist circumference versus placebo (all p < 0.001). Weight reduction with UBT251 was significantly greater than both placebo and semaglutide (all p < 0.05). Gastrointestinal events were the most common treatment-emergent adverse events. These findings support further phase 3 evaluation of UBT251. Registration: CTR20250029; NCT07163624.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"96 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149248493","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}
Pub Date : 2026-10-22DOI: 10.1016/j.cmet.2026.09.011
Max C. Petersen,Gordon I. Smith,Samuel Klein
{"title":"Response to Magkos and Silva: Diet macronutrient content and metabolic function in metabolically unhealthy obesity","authors":"Max C. Petersen,Gordon I. Smith,Samuel Klein","doi":"10.1016/j.cmet.2026.09.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.09.011","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"2 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149230118","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}
Pub Date : 2026-10-22DOI: 10.1016/j.cmet.2026.09.010
Faidon Magkos
{"title":"On the interpretation of diet-specific metabolic effects following weight loss","authors":"Faidon Magkos","doi":"10.1016/j.cmet.2026.09.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.09.010","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"19 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149230045","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}
Pub Date : 2026-10-21DOI: 10.1016/j.cmet.2026.09.017
Moritz V. Warmbrunn,Valeria Tosti,Raaj Kishore Biswas,Beatrice Bertozzi,Maria Lastra Cagigas,Nicola Veronese,Francesco Spelta,Laura Piccio,Richard D. Head,Richard R. Rodrigues,Dayna S. Early,Yanjiao Zhou,Giorgio Trinchieri,Giovanni Fiorito,Luigi Fontana
Whether the anti-inflammatory effects of a Mediterranean diet reflect diet quality itself or accompanying weight loss is unclear. In a 16-week randomized controlled-feeding trial, 53 adults (77% female; mean age 54.7 years) with metabolic risk factors received a fully provided Mediterranean diet or their habitual western diet for 8 weeks, then added twice-weekly fasting days for a further 8 weeks. The primary outcome, high-sensitivity C-reactive protein, did not change during the diet-only phase despite clear dietary separation. After fasting began, C-reactive protein fell in the Mediterranean-diet group relative to controls, alongside greater weight loss, improved insulin sensitivity, and lower blood pressure; lipid improvements had already emerged during the diet-only phase. Multi-omic analyses showed parallel reductions in inflammatory signaling, with gut microbiome composition largely stable. Thus, diet quality alone does not lower inflammation over 8 weeks; negative energy balance and weight loss during fasting appear to be the stronger drivers. This study was registered at ClinicalTrials.gov (NCT02148458).
{"title":"Weight loss during intermittent fasting, not Mediterranean diet quality alone, is associated with lower inflammation: A randomized controlled trial","authors":"Moritz V. Warmbrunn,Valeria Tosti,Raaj Kishore Biswas,Beatrice Bertozzi,Maria Lastra Cagigas,Nicola Veronese,Francesco Spelta,Laura Piccio,Richard D. Head,Richard R. Rodrigues,Dayna S. Early,Yanjiao Zhou,Giorgio Trinchieri,Giovanni Fiorito,Luigi Fontana","doi":"10.1016/j.cmet.2026.09.017","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.09.017","url":null,"abstract":"Whether the anti-inflammatory effects of a Mediterranean diet reflect diet quality itself or accompanying weight loss is unclear. In a 16-week randomized controlled-feeding trial, 53 adults (77% female; mean age 54.7 years) with metabolic risk factors received a fully provided Mediterranean diet or their habitual western diet for 8 weeks, then added twice-weekly fasting days for a further 8 weeks. The primary outcome, high-sensitivity C-reactive protein, did not change during the diet-only phase despite clear dietary separation. After fasting began, C-reactive protein fell in the Mediterranean-diet group relative to controls, alongside greater weight loss, improved insulin sensitivity, and lower blood pressure; lipid improvements had already emerged during the diet-only phase. Multi-omic analyses showed parallel reductions in inflammatory signaling, with gut microbiome composition largely stable. Thus, diet quality alone does not lower inflammation over 8 weeks; negative energy balance and weight loss during fasting appear to be the stronger drivers. This study was registered at ClinicalTrials.gov (NCT02148458).","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"3 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225923","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}
Defective tumor antigen presentation promotes immune evasion and resistance to immune checkpoint blockade. Here, we identified the short-chain fatty acid propionate as a potent enhancer of major histocompatibility complex class I (MHC class I) antigen presentation. Propionate stabilizes MHC class I on tumor cells, promotes CD8+ T cell infiltration and activation, and suppresses tumor growth. Mechanistically, the E3 ubiquitin (Ub) ligase STUB1 directly interacts with human leukocyte antigen (HLA)-A to mediate K168/K170 polyubiquitination and subsequent degradation. Propionate directly binds STUB1 through hydrogen bonds involving K30 and N34, residues that overlap with the MHC class I-binding interface. This interaction blocks STUB1-mediated MHC class I polyubiquitination, thereby stabilizing MHC class I, enhancing T cell receptor (TCR) engagement and T cell activation, and restraining tumor growth. Importantly, propionate or the propionate-producing probiotic Akkermansia muciniphila markedly enhanced anti-PD-1 efficacy. These findings uncover a non-metabolic moonlighting function of short-chain fatty acids in regulating tumor immunity and provide a rationale for leveraging dietary propionate or propionate-producing probiotics to enhance immune checkpoint therapy.
{"title":"Propionate promotes MHC class I antigen presentation and anti-tumor immunity","authors":"Suyao Li,Dong Guo,Qingqing Yang,Yizhi Cao,Yu Dong,Xiaoming Jiang,Xinyao Tian,Dou Nie,Lihui Wu,Qingang Wu,Xuxiao He,Yanyan Hu,Rongxuan Zhu,Ning Zhu,Shudi Luo,Yinan Shen,Yuhao Wang,Zhexu Chi,Ying Yuan,Daqian Xu,Weilin Wang,Yuan Ding,Zhimin Lu","doi":"10.1016/j.cmet.2026.09.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.09.018","url":null,"abstract":"Defective tumor antigen presentation promotes immune evasion and resistance to immune checkpoint blockade. Here, we identified the short-chain fatty acid propionate as a potent enhancer of major histocompatibility complex class I (MHC class I) antigen presentation. Propionate stabilizes MHC class I on tumor cells, promotes CD8+ T cell infiltration and activation, and suppresses tumor growth. Mechanistically, the E3 ubiquitin (Ub) ligase STUB1 directly interacts with human leukocyte antigen (HLA)-A to mediate K168/K170 polyubiquitination and subsequent degradation. Propionate directly binds STUB1 through hydrogen bonds involving K30 and N34, residues that overlap with the MHC class I-binding interface. This interaction blocks STUB1-mediated MHC class I polyubiquitination, thereby stabilizing MHC class I, enhancing T cell receptor (TCR) engagement and T cell activation, and restraining tumor growth. Importantly, propionate or the propionate-producing probiotic Akkermansia muciniphila markedly enhanced anti-PD-1 efficacy. These findings uncover a non-metabolic moonlighting function of short-chain fatty acids in regulating tumor immunity and provide a rationale for leveraging dietary propionate or propionate-producing probiotics to enhance immune checkpoint therapy.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"12 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225922","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}
Nicotinamide adenine dinucleotide (NAD) occupies a privileged position at the intersection of cellular bioenergetics, redox homeostasis, and signal transduction. Beyond its canonical role in ATP synthesis, NAD serves as an obligate cofactor for enzymes including poly(ADP-ribose) polymerases (PARPs), sirtuins, and CD38, thereby regulating DNA repair, epigenetic remodeling, and inflammatory signaling. Thus, NAD metabolism supports the preservation of cellular homeostasis against oncogenic insults. Malignant transformation, however, imposes substantial biosynthetic and genotoxic stress, often driving metabolic adaptations that amplify NAD production via nicotinamide phosphoribosyltransferase (NAMPT). This endows cancer cells with enhanced proliferative capacity, stress tolerance, and immunoevasive features. Importantly, the dependence of malignant cells on sustained NAD availability constitutes a therapeutically exploitable vulnerability. Accordingly, NAMPT inhibitors, PARP inhibitors, and strategies targeting NAD-consuming ectoenzymes have shown preclinical and, in select settings, clinical efficacy. Here, we critically review the rewiring of NAD metabolism in cancer, associated therapeutic opportunities, and barriers to their clinical exploitation.
{"title":"A context-dependent framework for targeting NAD metabolism in cancer","authors":"Leire Arrizabalaga,Laura Santambrogio,Guido Kroemer,Lorenzo Galluzzi,Aitziber Buqué","doi":"10.1016/j.cmet.2026.09.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2026.09.015","url":null,"abstract":"Nicotinamide adenine dinucleotide (NAD) occupies a privileged position at the intersection of cellular bioenergetics, redox homeostasis, and signal transduction. Beyond its canonical role in ATP synthesis, NAD serves as an obligate cofactor for enzymes including poly(ADP-ribose) polymerases (PARPs), sirtuins, and CD38, thereby regulating DNA repair, epigenetic remodeling, and inflammatory signaling. Thus, NAD metabolism supports the preservation of cellular homeostasis against oncogenic insults. Malignant transformation, however, imposes substantial biosynthetic and genotoxic stress, often driving metabolic adaptations that amplify NAD production via nicotinamide phosphoribosyltransferase (NAMPT). This endows cancer cells with enhanced proliferative capacity, stress tolerance, and immunoevasive features. Importantly, the dependence of malignant cells on sustained NAD availability constitutes a therapeutically exploitable vulnerability. Accordingly, NAMPT inhibitors, PARP inhibitors, and strategies targeting NAD-consuming ectoenzymes have shown preclinical and, in select settings, clinical efficacy. Here, we critically review the rewiring of NAD metabolism in cancer, associated therapeutic opportunities, and barriers to their clinical exploitation.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"19 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173067","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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