{"title":"Fasting-induced ketogenesis sensitizes bacteria to antibiotic treatment","authors":"Shujun Cui, Danyang Chong, Yi-Xin Wang, Huixian Tong, Minggui Wang, Guo-Ping Zhao, Liang-Dong Lyu","doi":"10.1016/j.cmet.2025.04.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.006","url":null,"abstract":"Fasting metabolism is a commonly observed motivational response to acute infections and is conceptualized as being beneficial for host survival. Here, we show that fasting potentiates antibiotic treatment for murine sepsis caused by <em>Salmonella</em> Typhimurium, <em>Klebsiella pneumoniae</em>, and <em>Enterobacter cloacae</em>, resulting in increased bacterial clearance and improved host immune responses and survival. This effect is mediated by fasting-induced ketogenesis and could be alternatively implemented by combination therapy with antibiotics and ketone bodies. We show that the ketone body acetoacetate is an effector that sensitizes bacteria to antibiotic treatment by increasing antibiotic lethality and outer and inner membrane permeability. Our results demonstrate that acetoacetate depletes bacterial amino acids, particularly positively charged amino acids and putrescine, leading to cell membrane malfunctions and redox-related lethality. This study reveals an unrecognized role of ketogenesis in antibiotic treatment and a potential ketone body-based treatment strategy for bacterial sepsis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"24 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893223","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 : 2025-05-01DOI: 10.1016/j.cmet.2025.04.007
Won-Suk Song, Xiyu Shen, Kang Du, Cuauhtemoc B. Ramirez, Sang Hee Park, Yang Cao, Johnny Le, Hosung Bae, Joohwan Kim, Yujin Chun, Nikki Joyce Khong, Marie Kim, Sunhee Jung, Wonsuk Choi, Miranda L. Lopez, Zaid Said, Zehan Song, Sang-Guk Lee, Dequina Nicholas, Yo Sasaki, Qin Yang
{"title":"Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline","authors":"Won-Suk Song, Xiyu Shen, Kang Du, Cuauhtemoc B. Ramirez, Sang Hee Park, Yang Cao, Johnny Le, Hosung Bae, Joohwan Kim, Yujin Chun, Nikki Joyce Khong, Marie Kim, Sunhee Jung, Wonsuk Choi, Miranda L. Lopez, Zaid Said, Zehan Song, Sang-Guk Lee, Dequina Nicholas, Yo Sasaki, Qin Yang","doi":"10.1016/j.cmet.2025.04.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.007","url":null,"abstract":"Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD<sup>+</sup>) catabolism primarily feeds systemic organs for NAD<sup>+</sup> synthesis. We surprisingly found that, despite blunted hepatic NAD<sup>+</sup> and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs’ NAD<sup>+</sup> are unaffected. Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). We further demonstrate cytosolic 5′-nucleotidase II (NT5C2) as the NaR-producing enzyme. The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD<sup>+</sup> through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide. Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD<sup>+</sup>, including kidneys, and reduces kidney inflammation and albuminuria. Thus, the liver-kidney axis maintains systemic NAD<sup>+</sup> homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD<sup>+</sup> decline and kidney dysfunction.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"91 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893224","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 : 2025-04-30DOI: 10.1016/j.cmet.2025.04.002
Sabina Chubanava, Iuliia Karavaeva, Amy M. Ehrlich, Roger M. Justicia, Astrid L. Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R. Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N. Rodrigues, Jesper F. Havelund, Farina L. Schlabs, Steen Larsen, Caio Y. Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Jonas T. Treebak
{"title":"NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging","authors":"Sabina Chubanava, Iuliia Karavaeva, Amy M. Ehrlich, Roger M. Justicia, Astrid L. Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R. Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N. Rodrigues, Jesper F. Havelund, Farina L. Schlabs, Steen Larsen, Caio Y. Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Jonas T. Treebak","doi":"10.1016/j.cmet.2025.04.002","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.002","url":null,"abstract":"Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD<sup>+</sup> biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD<sup>+</sup> abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"105 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889985","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 : 2025-04-29DOI: 10.1016/j.cmet.2025.04.012
Ying Liu, Huihui Mei, Li Xue, Chuanli Cheng, Yingtong Wu, Chao Zou, Ying Yu, Lin Gao, Huanan Zhang, Xinrui Gao, Qiang Li, Lu Wang, Jie Liu, Chaoqun Niu, Xueying Zhang, Sumei Hu, John R. Speakman
{"title":"Testing the carbohydrate-insulin model: Short-term metabolic responses to consumption of meals with varying glycemic index in healthy adults","authors":"Ying Liu, Huihui Mei, Li Xue, Chuanli Cheng, Yingtong Wu, Chao Zou, Ying Yu, Lin Gao, Huanan Zhang, Xinrui Gao, Qiang Li, Lu Wang, Jie Liu, Chaoqun Niu, Xueying Zhang, Sumei Hu, John R. Speakman","doi":"10.1016/j.cmet.2025.04.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.012","url":null,"abstract":"(Cell Metabolism <em>37</em>, 606–615.e1–e3; March 4, 2025)","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"36 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885420","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 : 2025-04-22DOI: 10.1016/j.cmet.2025.04.001
Yuki Tatekoshi, Amir Mahmoodzadeh, Jason S. Shapiro, Mingyang Liu, George M. Bianco, Ayumi Tatekoshi, Spencer Duncan Camp, Adam De Jesus, Navid Koleini, Santiago De La Torre, J. Andrew Wasserstrom, Wolfgang H. Dillmann, Benjamin R. Thomson, Kenneth C. Bedi, Kenneth B. Margulies, Samuel E. Weinberg, Hossein Ardehali
{"title":"Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction","authors":"Yuki Tatekoshi, Amir Mahmoodzadeh, Jason S. Shapiro, Mingyang Liu, George M. Bianco, Ayumi Tatekoshi, Spencer Duncan Camp, Adam De Jesus, Navid Koleini, Santiago De La Torre, J. Andrew Wasserstrom, Wolfgang H. Dillmann, Benjamin R. Thomson, Kenneth C. Bedi, Kenneth B. Margulies, Samuel E. Weinberg, Hossein Ardehali","doi":"10.1016/j.cmet.2025.04.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.04.001","url":null,"abstract":"Heart failure with preserved ejection fraction (HFpEF) is a common cause of morbidity and mortality worldwide, but its pathophysiology remains unclear. Here, we report a mouse model of HFpEF and show that hexokinase (HK)-1 mitochondrial binding in endothelial cells (ECs) is critical for protein O-GlcNAcylation and the development of HFpEF. We demonstrate increased mitochondrial dislocation of HK1 within ECs in HFpEF mice. Mice with deletion of the mitochondrial-binding domain of HK1 spontaneously develop HFpEF and display impaired angiogenesis. Spatial proximity of dislocated HK1 and O-linked N-acetylglucosamine transferase (OGT) causes increased OGT activity, shifting the balance of the hexosamine biosynthetic pathway intermediates into the O-GlcNAcylation machinery. EC-specific overexpression of O-GlcNAcase and an OGT inhibitor reverse angiogenic defects and the HFpEF phenotype, highlighting the importance of protein O-GlcNAcylation in the development of HFpEF. Our study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation, and provides a potential therapy for HFpEF.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"62 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857785","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 : 2025-04-22DOI: 10.1016/j.cmet.2025.03.017
Cuauhtemoc B. Ramirez, In Sook Ahn, Varvara I. Rubtsova, Ingrid Cely, Johnny Le, Joohwan Kim, Sunhee Jung, Miranda E. Kelly, Yeojin Kim, Hosung Bae, Won-Suk Song, Yasmine H. Alam, Guanglin Zhang, Graciel Diamante, Alina Chao, Lauren Hoffner, Alexis Anica, Izabelle Le, Miranda L. Lopez, Ian J. Tamburini, Cholsoon Jang
{"title":"Circulating glycerate predicts resilience to fructose-induced hepatic steatosis","authors":"Cuauhtemoc B. Ramirez, In Sook Ahn, Varvara I. Rubtsova, Ingrid Cely, Johnny Le, Joohwan Kim, Sunhee Jung, Miranda E. Kelly, Yeojin Kim, Hosung Bae, Won-Suk Song, Yasmine H. Alam, Guanglin Zhang, Graciel Diamante, Alina Chao, Lauren Hoffner, Alexis Anica, Izabelle Le, Miranda L. Lopez, Ian J. Tamburini, Cholsoon Jang","doi":"10.1016/j.cmet.2025.03.017","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.03.017","url":null,"abstract":"Excessive intake of dietary fructose increases the risk of metabolic-dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and cancers. However, what host factors determine disease vulnerability is incompletely understood. Here, we leverage genetically divergent mouse strains, mass spectrometry-based metabolomics, and <em>in vivo</em> isotope tracing, identifying circulating glycerate as a biomarker that predicts resilience to fructose-induced hepatic steatosis in both sexes. We found that the surge of circulating glycerate after an oral fructose provision reflects strong small-intestinal fructose catabolism. Such fructose clearance by the small intestine is linked to a weaker induction of hepatic <em>de novo</em> lipogenesis and steatosis upon chronic fructose exposure across strains. These data indicate the potential utility of an oral fructose tolerance test and circulating glycerate measurements to predict an individual's susceptibility to fructose-elicited steatotic liver and provide personalized dietary recommendations.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"35 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857781","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 : 2025-04-16DOI: 10.1016/j.cmet.2025.03.015
Baiyu He, Kyle D. Copps, Oliver Stöhr, Beikl Liu, Songhua Hu, Shakchhi Joshi, Marcia C. Haigis, Morris F. White, Hao Zhu, Rongya Tao
{"title":"Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling","authors":"Baiyu He, Kyle D. Copps, Oliver Stöhr, Beikl Liu, Songhua Hu, Shakchhi Joshi, Marcia C. Haigis, Morris F. White, Hao Zhu, Rongya Tao","doi":"10.1016/j.cmet.2025.03.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.03.015","url":null,"abstract":"Hepatic insulin sensitivity is critical for systemic glucose and lipid homeostasis. The liver is spatially organized into zones in which hepatocytes express distinct metabolic enzymes; however, the functional significance of this zonation to metabolic dysregulation caused by insulin resistance is undetermined. Here, we used CreER mice to selectively disrupt insulin signaling in periportal (PP) and pericentral (PC) hepatocytes. PP-insulin resistance has been suggested to drive combined hyperglycemia and excess lipogenesis in individuals with type 2 diabetes. However, PP-insulin resistance in mice impaired lipogenesis and suppressed high-fat diet (HFD)-induced hepatosteatosis, despite elevated gluconeogenesis and insulin. In contrast, PC-insulin resistance reduced HFD-induced PC steatosis while preserving normal glucose homeostasis, in part by shifting glycolytic metabolism from the liver to the muscle. These results demonstrate distinct roles of insulin in PP versus PC hepatocytes and suggest that PC-insulin resistance might be therapeutically useful to combat hepatosteatosis without compromising glucose homeostasis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"21 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837037","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 : 2025-04-14DOI: 10.1016/j.cmet.2025.03.014
Xinxin Song, Zhuan Zhou, Jiao Liu, Jingbo Li, Chunhua Yu, Herbert J. Zeh, Daniel J. Klionsky, Brent R. Stockwell, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang
{"title":"Cytosolic cytochrome c represses ferroptosis","authors":"Xinxin Song, Zhuan Zhou, Jiao Liu, Jingbo Li, Chunhua Yu, Herbert J. Zeh, Daniel J. Klionsky, Brent R. Stockwell, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang","doi":"10.1016/j.cmet.2025.03.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.03.014","url":null,"abstract":"The release of cytochrome <em>c</em>, somatic (CYCS) from mitochondria to the cytosol is an established trigger of caspase-dependent apoptosis. Here, we unveil an unexpected role for cytosolic CYCS in inhibiting ferroptosis—a form of oxidative cell death driven by uncontrolled lipid peroxidation. Mass spectrometry and site-directed mutagenesis revealed the existence of a cytosolic complex composed of inositol polyphosphate-4-phosphatase type I A (INPP4A) and CYCS. This CYCS-INPP4A complex is distinct from the CYCS-apoptotic peptidase activating factor 1 (APAF1)-caspase-9 apoptosome formed during mitochondrial apoptosis. CYCS boosts INPP4A activity, leading to increased formation of phosphatidylinositol-3-phosphate, which prevents phospholipid peroxidation and plasma membrane rupture, thus averting ferroptotic cell death. Unbiased screening led to the identification of the small-molecule compound 10A3, which disrupts the CYCS-INPP4A interaction. 10A3 sensitized cultured cells and tumors implanted in immunocompetent mice to ferroptosis. Collectively, these findings redefine our understanding of cytosolic CYCS complexes that govern diverse cell death pathways.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"6 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827149","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 : 2025-04-11DOI: 10.1016/j.cmet.2025.03.013
Ludovica Cotellessa, Veronica Sobrino, Mauro S.B. Silva, Maxime Delit, Hélène Maitre, Emilie Caron, Gaëtan Ternier, Natalia da Silva Lima, Tori Lhomme, Frank Giton, Andrea Sorrentino, Laura Carraresi, Giovanna Di Nardo, Ruben Nogueiras, Manuel Tena-Sempere, Vincent Prevot, Paolo Giacobini
{"title":"Preventing and correcting polycystic ovary syndrome by targeting anti-Müllerian hormone signaling in minipuberty and adulthood in mice","authors":"Ludovica Cotellessa, Veronica Sobrino, Mauro S.B. Silva, Maxime Delit, Hélène Maitre, Emilie Caron, Gaëtan Ternier, Natalia da Silva Lima, Tori Lhomme, Frank Giton, Andrea Sorrentino, Laura Carraresi, Giovanna Di Nardo, Ruben Nogueiras, Manuel Tena-Sempere, Vincent Prevot, Paolo Giacobini","doi":"10.1016/j.cmet.2025.03.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.03.013","url":null,"abstract":"Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, causes significant reproductive and metabolic comorbidities, with no current cure. Gestational androgen and anti-Müllerian hormone (AMH) excess are linked to PCOS, and prenatal aberrant exposure to these hormones induces PCOS-like traits in animal models. However, whether the AMH effects on PCOS programming could extend to early postnatal life remains unknown. Clinical observations showed higher AMH levels during minipuberty in infants of mothers with PCOS, but whether this contributes to PCOS development is uncertain. Here, we show that exposure to high AMH levels during minipuberty in mice causes PCOS-like reproductive and metabolic defects in both sexes. A neutralizing antibody targeting AMH receptor 2 (AMHR2) prevented these defects when administered during minipuberty and alleviated symptoms when given in adulthood. These findings highlight the causal role of elevated AMH in PCOS and suggest AMHR2-targeting therapy as a potential preventive or curative approach.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"0 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819965","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":"Targeted tumor therapy with L-cyst(e)ine-addicted bacteria-nanodrug biohybrids","authors":"Yu-Zhang Wang, Wei-Hai Chen, Zi-Yi Han, Shi-Man Zhang, Ping Ji, Cheng Zhang, Jun-Long Liang, Xian-Zheng Zhang","doi":"10.1016/j.cmet.2025.03.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.03.012","url":null,"abstract":"Bacteria-based metabolic therapy has been acknowledged as a promising strategy for tumor treatment. However, the insufficient efficiency of wild-type bacteria severely restricts their therapeutic efficacy. Here, we elaborately develop an ʟ-cyst(e)ine-addicted bacteria-nanodrug biohybrid for metabolic therapy through a dual-selection directed evolution strategy. Our evolved strain exhibits a 36-fold increase in ʟ-cystine uptake and a 23-fold improvement in total activity of cysteine desulfhydrases compared with the wild-type strain. By conjugating with DMXAA-loaded liposomes, the engineered bacteria-nanodrug biohybrid not only prevents the influx of nutrients into the tumor by blocking neovasculature but also achieves efficient and durable CySS catabolism locally. The unavailable of Cys species disrupts redox homeostasis and strikingly increases intracellular ROS level, achieving favorable therapeutic outcomes in multiple tumor models. Our study not only highlights the promise of directed evolution strategy in enhancing the stability and efficiency of bacteria-based living biocatalyst but also provides new opportunities for antitumor metabolic therapy.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"43 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143814003","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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