Metabolism: clinical and experimental最新文献

{"title":"Insulin regulation of vessel wall function and hypertension in the metabolic syndrome; from bench to bedside and back again Revisiting the work of Dr. James R. Sowers","authors":"Adam Whaley-Connell , Guanghong Jia , Annayya R. Aroor , Ranganath Muniyappa , Michael A. Hill , Christos S. Mantzoros","doi":"10.1016/j.metabol.2025.156236","DOIUrl":"10.1016/j.metabol.2025.156236","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156236"},"PeriodicalIF":10.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eva1 deficiency prevents obesity-induced metabolic disorders by reducing visceral adipose dysfunction","authors":"You Lee Son ,&nbsp;Jiahui Hou ,&nbsp;Mira Kato-Suzuki ,&nbsp;Yuko Okamatsu-Ogura ,&nbsp;Megumi Watase ,&nbsp;Hiroshi Kiyonari ,&nbsp;Toru Kondo","doi":"10.1016/j.metabol.2025.156235","DOIUrl":"10.1016/j.metabol.2025.156235","url":null,"abstract":"<div><h3>Aims</h3><div>Epithelial V-like antigen 1 (Eva1) is a highly specific marker for brown adipose tissue (BAT) in both mice and humans, but its metabolic function remains unclear. We investigated the impact of Eva1 deletion on the development of obesity.</div></div><div><h3>Methods</h3><div>To assess the metabolic role of Eva1, we generated whole-body and adipocyte-specific Eva1^{knockout (KO)} mice, which were subjected to a high-fat diet (HFD) for 12 weeks and characterized metabolic phenotypes. To further elucidate the depot-dependent impact of Eva1 deficiency, we performed histological analysis and 3′ mRNA-seq of BAT and epididymal visceral white adipose tissue (eWAT). To investigate the role of macrophage-derived Eva1 in obesity development, we transplanted wild-type (WT) or Eva1^KO macrophages into Eva1^KO mice fed an HFD.</div></div><div><h3>Results</h3><div>We found that whole-body Eva1^KO mice are resistant to HFD-induced obesity, insulin resistance and visceral adipose inflammation. However, Eva1 deletion in adipocytes, both brown and white, did not phenocopy these protective effects. Notably, whole-body Eva1 deficiency triggers functional changes in eWAT, but not in BAT. These results led us to investigate a possible involvement of macrophages in Eva1-mediated obesity regulation. We found that Eva1 is expressed in macrophages and plays a role in lipopolysaccharide (LPS)-induced inflammatory responses, possibly through the direct interaction with toll-like receptor 4 (TLR4). Moreover, Eva1^KO mice exhibited improved survival rates in the face of severe sepsis induced by LPS. Importantly, transplantation of WT macrophages to Eva1^KO mice abolished the beneficial effects of whole-body Eva1 deletion against obesity and visceral adipose inflammation.</div></div><div><h3>Conclusion</h3><div>Our findings highlight macrophage-derived Eva1 as an important mediator in obesity-induced eWAT remodeling, suggesting that targeting Eva1 could offer a novel therapeutic strategy for obesity-related metabolic disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156235"},"PeriodicalIF":10.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prolonged increase in glutamate whole body and intracellular production in older adults with COPD and healthy controls post-resistance exercise","authors":"Robert H. Mbilinyi ,&nbsp;Nicolaas E.P. Deutz ,&nbsp;Clayton L. Cruthirds ,&nbsp;Laura E. Ruebush ,&nbsp;Tarun Sontam ,&nbsp;Gabriella A.M. Ten Have ,&nbsp;John J. Thaden ,&nbsp;Mariëlle P.K.J. Engelen","doi":"10.1016/j.metabol.2025.156185","DOIUrl":"10.1016/j.metabol.2025.156185","url":null,"abstract":"<div><h3>Background</h3><div>Exercise training is essential for pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD), yet patient responsiveness varies widely. We previously observed metabolic disturbances in amino acids critical for muscle health—such as glutamate, glutamine, branched-chain amino acids (BCAAs), and taurine—in COPD patients after an endurance exercise session, possibly related to increased energy demands and oxidative stress. However, the impact of resistance exercise on these metabolic pathways remains unclear.</div></div><div><h3>Methods</h3><div>We measured plasma concentration, whole-body production (WBP), and intracellular production of glutamate, glutamine, BCAAs, and taurine using stable isotope pulse techniques in 24 COPD and 25 healthy older participants. Measurements were obtained before, and at 1 and 24 h after, a resistance exercise session.</div></div><div><h3>Results</h3><div>At baseline, COPD participants exhibited lower WBP of glutamine, taurine, and BCAAs compared to healthy participants (<em>p</em> &lt; 0.05). Resistance exercise increased WBP of glutamate by 37–42 %, glutamine by 9–10 %, and intracellular glutamate production by 37–40 %, while decreasing WBP of taurine by 7 % (all <em>p</em> &lt; 0.0001). These effects persisted at 24 h post-exercise (<em>p</em> &lt; 0.05). Although WBP of BCAAs remained unchanged, plasma leucine and isoleucine levels decreased by 16 % and 13 %, respectively, in COPD participants post-exercise (<em>p</em> &lt; 0.05).</div></div><div><h3>Conclusions</h3><div>A single resistance exercise session alters glutamate-related metabolism for at least 24 h in healthy and COPD participants. A high BCAA clearance is likely required to rapidly upregulate glutamate production in COPD to meet increased energy demands, but this occurs at the cost of lowering plasma levels of BCAA necessary for muscle anabolism.</div></div><div><h3>Clinical trial registry</h3><div>Trial registration ClinicalTrials.gov: NCT02780219.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156185"},"PeriodicalIF":10.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Turning sour into sweet: Lactylation modification as a promising target in cardiovascular health","authors":"Yajie Liao ,&nbsp;Liyan Niu ,&nbsp;Jitao Ling ,&nbsp;Yuzhen Cui ,&nbsp;Zixuan Huang ,&nbsp;Jingdong Xu ,&nbsp;Yuan Jiang ,&nbsp;Peng Yu ,&nbsp;Xiao Liu","doi":"10.1016/j.metabol.2025.156234","DOIUrl":"10.1016/j.metabol.2025.156234","url":null,"abstract":"<div><div>Lactylation, a recently identified posttranslational modification (PTM), has emerged as a critical regulatory mechanism in cardiovascular diseases (CVDs). This PTM involves the addition of lactyl groups to lysine residues on histones and nonhistone proteins, influencing gene expression and cellular metabolism. The discovery of lactylation has revealed new directions for understanding metabolic and immune processes, particularly in the context of CVDs. This review describes the intricate roles of specific lactylated proteins and enzymes, such as H3K18, HMGB1, MCT1/4, and LDH, in the regulation of cardiovascular pathology. This study also highlights the unique impact of lactylation on myocardial hypertrophy and distinguishes it from other PTMs, such as SUMOylation and acetylation, underscoring its potential as a therapeutic target. Emerging drugs targeting lactate transporters and critical enzymes involved in lactylation offer promising avenues for novel CVD therapies. This review calls for further research to elucidate the mechanisms linking lactylation to CVDs, emphasizing the need for comprehensive studies at the molecular, cellular, and organismal levels to pave the way for innovative preventive, diagnostic, and treatment strategies in cardiovascular medicine.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156234"},"PeriodicalIF":10.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LINC00278 and BRG1: A key regulatory axis in male obesity and preadipocyte adipogenesis","authors":"Tongtong Zhang ,&nbsp;Zhengyun Ren ,&nbsp;Rui Mao ,&nbsp;Wei Yi ,&nbsp;Bin Wang ,&nbsp;Huawu Yang ,&nbsp;Haibo Wang ,&nbsp;Yanjun Liu","doi":"10.1016/j.metabol.2025.156194","DOIUrl":"10.1016/j.metabol.2025.156194","url":null,"abstract":"<div><div>Obesity is a significant public health concern directly associated with adipogenesis. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of adipogenesis. However, the roles of sex-specific lncRNAs in adipose tissue are not well comprehended. In this study, we used lncRNA microarrays to profile lncRNAs expression in visceral adipose tissues from obese and lean individuals, identifying LINC00278 as significantly and exclusively expressed in males. Elevated levels of LINC00278 were associated with higher body mass index (BMI) and non-remission after bariatric surgery in individuals with obesity. Mechanistic studies further revealed that METTL14 regulates the m⁶A methylation of LINC00278, which in turn binds with BRG1, activating the PPAR-γ2 pathway and promoting adipogenesis. Additionally, adipose-specific LINC00278 knock-in in C57BL/6 J mice resulted in adipocyte enlargement, increased body weight, higher body fat percentage, and impaired glucose metabolism. Treatment with the BRG1 inhibitor, BRM/BRG1 ATP Inhibitor-1, significantly alleviated the obesity phenotype in these mice. Our findings highlight the critical role of LINC00278 in male adipogenesis, suggesting that targeting the LINC00278-BRG1 axis could be a potential therapeutic strategy for managing obesity and related metabolic disorders in males.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156194"},"PeriodicalIF":10.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-metabolite signature robustly predicts long-term mortality in the PREDIMED trial and several US cohorts.","authors":"Gonzalo Fernández-Duval, Cristina Razquin, Fenglei Wang, Huan Yun, Jie Hu, Marta Guasch-Ferré, Kathryn Rexrode, Raji Balasubramanian, Jesús García-Gavilán, Miguel Ruiz-Canela, Clary B Clish, Dolores Corella, Enrique Gómez-Gracia, Miquel Fiol, Ramón Estruch, José Lapetra, Montse Fitó, Luis Serra-Majem, Emilio Ros, Liming Liang, Courtney Dennis, Eva M Asensio, Olga Castañer, Francisco J Planes, Jordi Salas-Salvadó, Frank B Hu, Estefanía Toledo, Miguel A Martínez-González","doi":"10.1016/j.metabol.2025.156195","DOIUrl":"10.1016/j.metabol.2025.156195","url":null,"abstract":"<p><p>Metabolome-based biomarkers contribute to identify mechanisms of disease and to a better understanding of overall mortality. In a long-term follow-up subsample (n = 1878) of the PREDIMED trial, among 337 candidate baseline plasma metabolites repeatedly assessed at baseline and after 1 year, 38 plasma metabolites were identified as predictors of all-cause mortality. Gamma-amino-butyric acid (GABA), homoarginine, serine, creatine, 1-methylnicotinamide and a set of sphingomyelins, plasmalogens, phosphatidylethanolamines and cholesterol esters were inversely associated with all-cause mortality, whereas plasma dimethylguanidino valeric acid (DMGV), choline, short and long-chain acylcarnitines, 4-acetamidobutanoate, pseudouridine, 7-methylguanine, N6-acetyllysine, phenylacetylglutamine and creatinine were associated with higher mortality. The multi-metabolite signature created as a linear combination of these selected metabolites, also showed a strong association with all-cause mortality using plasma samples collected at 1-year follow-up in PREDIMED. This association was subsequently confirmed in 4 independent American cohorts, validating the signature as a consistent predictor of all-cause mortality across diverse populations.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156195"},"PeriodicalIF":10.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining lipedema's molecular hallmarks by multi-omics approach for disease prediction in women","authors":"Leon G. Straub ,&nbsp;Jan-Bernd Funcke ,&nbsp;Nolwenn Joffin ,&nbsp;Chanmin Joung ,&nbsp;Sara Al-Ghadban ,&nbsp;Shangang Zhao ,&nbsp;Qingzhang Zhu ,&nbsp;Ilja L. Kruglikov ,&nbsp;Yi Zhu ,&nbsp;Paul R. Langlais ,&nbsp;Ruth Gordillo ,&nbsp;Karen L. Herbst ,&nbsp;Philipp E. Scherer","doi":"10.1016/j.metabol.2025.156191","DOIUrl":"10.1016/j.metabol.2025.156191","url":null,"abstract":"<div><div>Lipedema is a chronic disease in females characterized by pathologic subcutaneous adipose tissue expansion and hitherto remains without druggable targets. In this observational study, we investigated the molecular hallmarks of lipedema using an unbiased multi-omics approach. We found adipokine dysregulation in lipedema patients participating in a cross-sectional clinical study (<span><span>ClinicalTrial.gov</span><svg><path></path></svg></span>, <span><span>NCT02838277</span><svg><path></path></svg></span>), pointing towards the adipocyte as a key player. Analyses of newly generated transcriptomic (SRA, PRJNA940039) and proteomic (ProteomeXchange, <span><span>PXD058489</span><svg><path></path></svg></span>) datasets of early- and late-stage lipedema samples revealed a local downregulation of factors involved in inflammation. Concomitantly, factors involved in cellular respiration, oxidative phosphorylation, as well as in mitochondrial organization were upregulated. Measuring a cytokine and chemokine panel in the serum of non-menopausal women, we observed little systemic changes in inflammatory markers, but a trend towards increased VEGF. Metabolomic and lipidomic analyses highlighted altered circulating glutamic acid, glutathione, and sphingolipid levels, suggesting a broader dysregulation of metabolic and inflammatory processes. We subsequently benchmarked a set of models to accurately predict lipedema using serum factor measurements (sLPM). Our study of the molecular signature of lipedema thus provides not only potential targets for therapeutic intervention, but also candidate markers of disease development and progression.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156191"},"PeriodicalIF":10.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic dysfunction-associated steatotic liver disease: A sexually dimorphic disease and breast and gynecological cancer","authors":"Xinrong Zhang ,&nbsp;Mindie H. Nguyen","doi":"10.1016/j.metabol.2025.156190","DOIUrl":"10.1016/j.metabol.2025.156190","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global public health and economic burden worldwide in the past few decades. Epidemiological studies have shown that MASLD is a multisystem disease that is associated not only with liver-related complications but also with an increased risk of developing extrahepatic cancers. MASLD is a sexually dimorphic disease with sex hormones playing an important role in the development and progression of MASLD, especially by the levels and ratios of circulating estrogens and androgens. MASLD is associated with hormone-sensitive cancers including breast and gynecological cancer. The risk of breast and gynecological cancer is elevated in individuals with MASLD driven by shared metabolic risk factors including obesity and insulin resistance. Multiple potential mechanisms underline these associations including metabolic dysfunction, gut dysbiosis, chronic inflammation and dysregulated release of hepatokines. However, the effect of hormone therapy including hormone replacement therapy and anti-estrogen treatment on MASLD and female-specific cancers remains debatable at this time. This synopsis will review the associations between MASLD and breast and gynecological cancer, their underlying mechanisms, implications of hormonal therapies, and their future directions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156190"},"PeriodicalIF":10.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma metabolite profiles of meat intake and their association with cardiovascular disease risk: A population-based study in Swedish cohorts","authors":"Getachew Arage ,&nbsp;Koen F. Dekkers ,&nbsp;Luka Marko Rašo ,&nbsp;Ulf Hammar ,&nbsp;Ulrika Ericson ,&nbsp;Susanna C. Larsson ,&nbsp;Hanna Engel ,&nbsp;Gabriel Baldanzi ,&nbsp;Kamalita Pertiwi ,&nbsp;Sergi Sayols-Baixeras ,&nbsp;Rikard Landberg ,&nbsp;Johan Sundström ,&nbsp;J. Gustav Smith ,&nbsp;Gunnar Engström ,&nbsp;Johan Ärnlöv ,&nbsp;Marju Orho-Melander ,&nbsp;Lars Lind ,&nbsp;Tove Fall ,&nbsp;Shafqat Ahmad","doi":"10.1016/j.metabol.2025.156188","DOIUrl":"10.1016/j.metabol.2025.156188","url":null,"abstract":"<div><h3>Background</h3><div>Higher meat intake has been associated with adverse health outcomes, including cardiovascular disease (CVD). This study investigated plasma metabolites associated with meat intake and their relation with cardiometabolic biomarkers, subclinical CVD markers, and incident CVD.</div></div><div><h3>Methods</h3><div>Associations between self-reported meat intake and 1272 plasma metabolites were investigated in the SCAPIS cohort (<em>n</em> = 8,819; ages 50–64). Meat-associated metabolites were further examined for relation with subclinical CVD markers in the POEM cohort (<em>n</em> = 502; age 50) and incident CVD in the EpiHealth cohort (<em>n</em> = 2,278; ages 45–75; 107 incident cases over 9.6 years follow-up). Meat intake was categorized into white, unprocessed red, and processed red meat. Linear regression analyzed associations between meat intake, metabolites and cardiometabolic biomarkers, and subclinical CVD markers, while Cox models evaluated association between meat-associated metabolites and incident CVD.</div></div><div><h3>Results</h3><div>After correction for multiple testing, 458, 368, and 403 metabolites were associated with white, unprocessed red, and processed red meat, respectively. Processed red meat-associated metabolites were associated with higher levels of fasting insulin, hemoglobin A1c, and lipoprotein(a), and were inversely associated with maximal oxygen consumption. Two metabolites, 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (hazard ratios (HR: 1.32; 95 % CI: 1.08, 1.62)) and glutamine degradant (HR: 1.35; 95 % CI: 1.07, 1.72), that were inversely associated with intake of all meat types, were also associated with a higher risk of incident CVD.</div></div><div><h3>Conclusions</h3><div>This study provides comprehensive analysis of self-reported meat intake and plasma metabolites. The findings may enhance our understanding of the relationship between meat intake and CVD, and provide insights into underlying mechanisms.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156188"},"PeriodicalIF":10.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacologically targeting fatty acid synthase-mediated de novo lipogenesis alleviates osteolytic bone loss by directly inhibiting osteoclastogenesis through suppression of STAT3 palmitoylation and ROS signaling","authors":"Chunmei Xiu ,&nbsp;Lei Zhang ,&nbsp;Chenxi Zhang ,&nbsp;Yuannan Zhang ,&nbsp;Xi Luo ,&nbsp;Ziyi Zhang ,&nbsp;Hangkai Zhao ,&nbsp;Kaizhong Ji ,&nbsp;Zhiyuan Chen ,&nbsp;Guangxu He ,&nbsp;Jianquan Chen","doi":"10.1016/j.metabol.2025.156186","DOIUrl":"10.1016/j.metabol.2025.156186","url":null,"abstract":"<div><div>Aberrant increases in osteoclast formation and/or activity are the underlying cause of bone loss in a variety of osteolytic diseases. Fatty acid synthase (Fasn)-mediated <em>de novo</em> lipogenesis (<em>DNL</em>) is one of the major lipid metabolic pathways and has been shown to play critical roles in diverse physiological and pathological processes. However, little is known about its role in osteoclastogenesis. Here, we investigate the direct role of <em>DNL</em> in osteoclastogenesis and its therapeutic potential in osteolytic diseases. We found that <em>Fasn</em> expression and <em>DNL</em> levels are upregulated during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Inhibition of Fasn by <em>shRNA</em> knockdown or its pharmacological inhibitors (ASC40 and trans-C75) impairs osteoclast differentiation <em>in vitro</em>. Mechanistically, pharmacological inhibition of Fasn suppresses RANKL-induced c-Fos/NFATc1 expression and thus osteoclastogenesis partly by disrupting STAT3 palmitoylation, while promoting ROS scavenging to impair mitogen-activated protein kinase (MAPK) signaling. Finally, the therapeutic potential of ASC40 for the treatment of osteolytic bone loss is tested in two mouse models of osteolytic diseases, <em>i.e.</em> ovariectomy (OVX)-induced osteoporosis and titanium nanoparticle-induced calvarial osteolysis. The results show that ASC40 significantly attenuates bone loss and osteoclastogenesis in both models. In conclusion, our results demonstrate that Fasn-mediated <em>DNL</em> is a novel positive regulator of osteoclastogenesis and may serve as a promising therapeutic target for the treatment of osteoclast-driven osteolytic bone diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156186"},"PeriodicalIF":10.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}