Cell metabolismPub Date : 2025-02-27DOI: 10.1016/j.cmet.2025.01.018
Qionghua Cui, Shijin Li, Xidan Liu, Jie Liu, Wenxin Chen, Ye Sheng, Peng Xie, Li Jin, Fanxin Zeng, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao
{"title":"MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia","authors":"Qionghua Cui, Shijin Li, Xidan Liu, Jie Liu, Wenxin Chen, Ye Sheng, Peng Xie, Li Jin, Fanxin Zeng, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao","doi":"10.1016/j.cmet.2025.01.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.018","url":null,"abstract":"Both exercise and cancer can cause adipose tissue shrinkage. However, only cancer-associated weight loss, namely cachexia, is characterized by profound adipose inflammation and fibrosis. Here, we identified tumor-secreted macrophage migration inhibitory factor (MIF) as a major driver that skews the differentiation of adipose stem and progenitor cells (ASPCs) toward a pro-inflammatory and pro-fibrogenic direction, with reduced adipogenic capacity in cancer cachexia. By contrast, circulating MIF is moderately reduced after exercise. Mechanistically, atypical chemokine receptor 3 (ACKR3) in ASPCs serves as the predominant MIF receptor mediating its pathological effects. Inhibition of MIF by gene ablation in tumor cells or pharmacological blockade, as well as ASPC-specific <em>Ackr3</em> deficiency, markedly alleviates tumor-induced cachexia. These findings unveil MIF-ACKR3 signaling as a critical link between tumors and cachectic manifestations, providing a promising therapeutic target for cancer cachexia.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"35 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507257","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 : 2025-02-26DOI: 10.1016/j.cmet.2025.01.016
Jie Jiang, Yuqing Gao, Jiang Wang, Yan Huang, Rong Yang, Yongxin Zhang, Yuandi Ma, Yingquan Wen, Gongkai Luo, Shurui Zhang, Yutang Cao, Minjun Yu, Qinxue Wang, Shulei Hu, Kanglong Wang, Xiaozhen Guo, Frank J. Gonzalez, Yameng Liu, Hong Liu, Qing Xie, Cen Xie
{"title":"Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism","authors":"Jie Jiang, Yuqing Gao, Jiang Wang, Yan Huang, Rong Yang, Yongxin Zhang, Yuandi Ma, Yingquan Wen, Gongkai Luo, Shurui Zhang, Yutang Cao, Minjun Yu, Qinxue Wang, Shulei Hu, Kanglong Wang, Xiaozhen Guo, Frank J. Gonzalez, Yameng Liu, Hong Liu, Qing Xie, Cen Xie","doi":"10.1016/j.cmet.2025.01.016","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.016","url":null,"abstract":"Metabolic-dysfunction-associated steatohepatitis (MASH) remains a major health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific <em>Smpd3</em> gene disruption or pharmacological inhibition of SMPD3 alleviates MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. Although healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses sirtuin 1 (SIRT1), triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes disease progression by enhancing caveolae-dependent lipid uptake and extracellular vesicle secretion from steatotic hepatocytes to exacerbate inflammation and fibrosis. Consequently, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid metabolism and holds great promise for developing novel MASH therapies.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"24 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495774","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":"EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis","authors":"Fanglin Ma, Miriam Longo, Marica Meroni, Dipankar Bhattacharya, Erika Paolini, Shama Mughal, Syed Hussain, Sumit Kumar Anand, Neha Gupta, Yiwei Zhu, Amaia Navarro-Corcuera, Kenneth Li, Satya Prakash, Bruno Cogliati, Shuang Wang, Xin Huang, Xiaobo Wang, Arif Yurdagul, Oren Rom, Liheng Wang, Bishuang Cai","doi":"10.1016/j.cmet.2025.01.020","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.020","url":null,"abstract":"Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show that human fibrotic MASH livers have decreased EH-domain-binding protein 1 (EHBP1), a genome-wide association study (GWAS) locus associated with low-density lipoprotein (LDL) cholesterol, and that EHBP1 loss- and gain-of-function increase and decrease MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin-mediated PCSK9 secretion, leading to LDL receptor (LDLR) degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. At a cellular level, EHBP1 deficiency affects the intracellular localization of retromer, a protein complex required for sortilin stabilization. Our therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the tumor necrosis factor alpha (TNF-α)/peroxisome proliferator-activated receptor alpha (PPARα) pathway suppresses EHBP1 in MASH. These data not only provide mechanistic insights into the role of EHBP1 in cholesterol metabolism and MASH fibrosis but also elucidate an interplay between inflammation and EHBP1-mediated cholesterol metabolism.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"27 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495773","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":"AKR1D1 suppresses liver cancer progression by promoting bile acid metabolism-mediated NK cell cytotoxicity","authors":"Haoran Wei, Caixia Suo, Xuemei Gu, Shengqi Shen, Kashuai Lin, Chuxu Zhu, Kai Yan, Zhenhua Bian, Liang Chen, Tong Zhang, Ronghui Yan, Zhiyi Yang, Yingxuan Yu, Zhikun Li, Rui Liu, Junming He, Qiwei He, Xiuying Zhong, Weidong Jia, Chun-Ming Wong, Ping Gao","doi":"10.1016/j.cmet.2025.01.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.011","url":null,"abstract":"Bile acid metabolism and antitumor immunity are both disrupted during liver cancer progression. However, the complex regulatory relationship between them remains largely unclear. Here, we find that loss of aldo-keto reductase 1D1 (AKR1D1) promotes the accumulation of isolithocholic acid (iso-LCA) through gut microbiome dysregulation, thereby impairing the cytotoxic function of natural killer (NK) cells and leading to the accelerated development of hepatocellular carcinoma (HCC). Mechanistically, AKR1D1 deficiency leads to an increased proportion of <em>Bacteroidetes ovatus</em> (<em>B. ovatus</em>), which breaks down chenodeoxycholic acid (CDCA) into iso-LCA. Moreover, accumulated iso-LCA impairs the antitumor activity of hepatic NK cells in a phosphorylated-CREB1 (p-CREB1)-dependent manner. The potassium-sparing diuretic spironolactone treatment significantly enhances the inhibitory effect of anti-PD1 antibody on HCC progression by targeting iso-LCA-mediated tumor immune escape. Taken together, our results uncover a previously unappreciated link between AKR1D1 and HCC and suggest that targeting iso-LCA produced by <em>B. ovatus</em> might be a promising strategy to activate NK cell cytotoxicity to treat HCC.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"28 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486524","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 : 2025-02-24DOI: 10.1016/j.cmet.2025.01.017
Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Maria Eugenia Soriano
{"title":"MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling","authors":"Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Maria Eugenia Soriano","doi":"10.1016/j.cmet.2025.01.017","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.017","url":null,"abstract":"Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"8 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477752","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":"Caloric restriction prevents inheritance of polycystic ovary syndrome through oocyte-mediated DNA methylation reprogramming","authors":"Yue Liu, Yi Dong, Yonghui Jiang, Shan Han, Xin Liu, Xin Xu, Aiqing Zhu, Zihe Zhao, Yuan Gao, Yang Zou, Chuanxin Zhang, Yuehong Bian, Yuqing Zhang, Jiang Liu, Shigang Zhao, Han Zhao, Zi-Jiang Chen","doi":"10.1016/j.cmet.2025.01.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.014","url":null,"abstract":"Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing <em>in vitro</em> fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., <em>Adcy3</em>, <em>Gnas</em>, and <em>Srebf1</em>) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"25 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463087","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 : 2025-02-21DOI: 10.1016/j.cmet.2025.01.025
Caterina Miro, Annunziata Gaetana Cicatiello, Annarita Nappi, Serena Sagliocchi, Lucia Acampora, Federica Restolfer, Ornella Cuomo, Giulia de Alteris, Gabriella Pugliese, Sepehr Torabinejad, Rosa Maritato, Melania Murolo, Emery Di Cicco, Nunzio Velotti, Marianna Capuano, Evelina La Civita, Daniela Terracciano, Roberto Ciampaglia, Mariano Stornaiuolo, Mario Musella, Monica Dentice
{"title":"Leptin enhances the intracellular thyroid hormone activation in skeletal muscle to boost energy balance","authors":"Caterina Miro, Annunziata Gaetana Cicatiello, Annarita Nappi, Serena Sagliocchi, Lucia Acampora, Federica Restolfer, Ornella Cuomo, Giulia de Alteris, Gabriella Pugliese, Sepehr Torabinejad, Rosa Maritato, Melania Murolo, Emery Di Cicco, Nunzio Velotti, Marianna Capuano, Evelina La Civita, Daniela Terracciano, Roberto Ciampaglia, Mariano Stornaiuolo, Mario Musella, Monica Dentice","doi":"10.1016/j.cmet.2025.01.025","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.025","url":null,"abstract":"Thyroid hormones (THs) are key modulators of energy metabolism and cross-talk with other endocrine and metabolic factors. Notably, leptin can increase hypothalamic control of TH synthesis as an adaptive metabolic response regulating body weight. In this study, we found that the TH signal is heightened in overweight humans and is lost with obesity. In mice, systemic and intracerebroventricular leptin injection induces the expression of type 2 deiodinase (D2), the TH-activating enzyme, in skeletal muscle. Mechanistically, leptin enhances the transcription of D2 by a STAT3- and α-melanocyte-stimulating hormone (α-MSH)/cyclic AMP (cAMP)-dependent regulation. Notably, mice lacking D2 or with a mutation in the TH receptor do not exhibit the metabolic effects of leptin, such as increased insulin sensitivity and oxygen consumption, indicating that leptin’s peripheral metabolic effects in skeletal muscle are mediated by TH. These findings underscore the critical role of leptin in integrating the TH-induced metabolic activation, while also contributing to appetite suppression in response to perceived fat stores.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"50 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463088","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 : 2025-02-20DOI: 10.1016/j.cmet.2025.01.012
Jiawei Zhong, Danae Zareifi, Sophie Weinbrenner, Mattias Hansen, Felix Klingelhuber, Pamela A. Nono Nankam, Scott Frendo-Cumbo, Nayanika Bhalla, Lina Cordeddu, Thais de Castro Barbosa, Peter Arner, Ingrid Dahlman, Maheswary Muniandy, Sini Heinonen, Kirsi H. Pietiläinen, Anne Hoffmann, Adhideb Ghosh, Dorit John, Anke Tönjes, Patrik L. Ståhl, Mikael Rydén
{"title":"adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue","authors":"Jiawei Zhong, Danae Zareifi, Sophie Weinbrenner, Mattias Hansen, Felix Klingelhuber, Pamela A. Nono Nankam, Scott Frendo-Cumbo, Nayanika Bhalla, Lina Cordeddu, Thais de Castro Barbosa, Peter Arner, Ingrid Dahlman, Maheswary Muniandy, Sini Heinonen, Kirsi H. Pietiläinen, Anne Hoffmann, Adhideb Ghosh, Dorit John, Anke Tönjes, Patrik L. Ståhl, Mikael Rydén","doi":"10.1016/j.cmet.2025.01.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.012","url":null,"abstract":"We developed the Adipose Tissue Knowledge Portal by centralizing previously dispersed datasets, integrating clinical and experimental results with transcriptomic and proteomic data from >6,000 women and men. The platform includes multiple adipose depots, resident cell types, and adipocyte perturbation studies. By providing streamlined data access, the portal enables integrative analyses and serves as a powerful tool to interrogate various dimensions of adipose biology down to the single-cell level.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"310 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451886","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 : 2025-02-20DOI: 10.1016/j.cmet.2025.01.008
Bo Yuan, Will Doxsey, Özlem Tok, Young-Yon Kwon, Yanshan Liang, Karen E. Inouye, Gökhan S. Hotamışlıgil, Sheng Hui
{"title":"An organism-level quantitative flux model of energy metabolism in mice","authors":"Bo Yuan, Will Doxsey, Özlem Tok, Young-Yon Kwon, Yanshan Liang, Karen E. Inouye, Gökhan S. Hotamışlıgil, Sheng Hui","doi":"10.1016/j.cmet.2025.01.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.008","url":null,"abstract":"Mammalian tissues feed on nutrients in the blood circulation. At the organism level, mammalian energy metabolism is comprised of the oxidation, storage, interconversion, and release of circulating nutrients. Here, by integrating isotope tracer infusion, mass spectrometry, and isotope gas analyzer measurement, we developed a framework to systematically quantify fluxes through these metabolic processes for 10 major circulating energy nutrients in mice, resulting in an organism-level quantitative flux model of energy metabolism. This model revealed in wild-type mice that circulating nutrients have metabolic cycling fluxes dominant to their oxidation fluxes, with distinct partitions between cycling and oxidation for individual circulating nutrients. Applications of this framework in obese mouse models showed extensive elevation of metabolic cycling fluxes in ob/ob mice but not in diet-induced obese mice on a per-animal or per-lean mass basis. Our framework is a valuable tool to reveal new features of energy metabolism in physiological and disease conditions.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"4 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451882","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 : 2025-02-19DOI: 10.1016/j.cmet.2025.01.007
Zhenyu Wang, Li Tian, Yi Jiang, Lijun Ning, Xiaoqiang Zhu, Xuejie Chen, Baoqin Xuan, Yilu Zhou, Jinmei Ding, Yanru Ma, Ying Zhao, Xiaowen Huang, Muni Hu, Jing-Yuan Fang, Nan Shen, Zhijun Cao, Haoyan Chen, Xiaoyan Wang, Jie Hong
{"title":"Synergistic role of gut-microbial L-ornithine in enhancing ustekinumab efficacy for Crohn’s disease","authors":"Zhenyu Wang, Li Tian, Yi Jiang, Lijun Ning, Xiaoqiang Zhu, Xuejie Chen, Baoqin Xuan, Yilu Zhou, Jinmei Ding, Yanru Ma, Ying Zhao, Xiaowen Huang, Muni Hu, Jing-Yuan Fang, Nan Shen, Zhijun Cao, Haoyan Chen, Xiaoyan Wang, Jie Hong","doi":"10.1016/j.cmet.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.007","url":null,"abstract":"The role of the intestinal microbiome in Crohn’s disease (CD) treatment remains poorly understood. This study investigates microbe-host interactions in CD patients undergoing ustekinumab (UST) therapy. Fecal metagenome, metabolome, and host transcriptome data from 85 CD patients were analyzed using multi-omics integration and mediation analysis. Our findings reveal significant microbiome-metabolite-host interactions. Specifically, <em>Faecalibacterium prausnitzii</em> was linked to altered L-ornithine biosynthesis, resulting in higher L-ornithine levels in patients before UST therapy. <em>In vivo</em> and <em>in vitro</em> studies demonstrated that microbiome-derived L-ornithine enhances UST treatment sensitivity in CD by disrupting the host IL-23 receptor signaling and inhibiting Th17 cell stabilization through the IL-12RB1/TYK2/STAT3 axis. L-ornithine significantly enhances the therapeutic efficacy of UST in CD patients, as demonstrated in a prospective clinical trial. These findings suggest that targeting specific microbe-host metabolic pathways may improve the efficacy of inflammatory bowel disease (IBD) treatments.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"2 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452146","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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