Metabolism: clinical and experimental最新文献

{"title":"HMGCS2 desuccinylation modulates acetoacetate to drive tubule-macrophage inflammatory crosstalk in diabetic kidney disease","authors":"Ziyue Lin ,&nbsp;Dan Lv ,&nbsp;He Zha ,&nbsp;Handeng Liu ,&nbsp;Rui Peng ,&nbsp;Jiakun Yang ,&nbsp;Wuchao Li ,&nbsp;Xiaohui Liao ,&nbsp;Yan Sun ,&nbsp;Zheng Zhang","doi":"10.1016/j.metabol.2026.156510","DOIUrl":"10.1016/j.metabol.2026.156510","url":null,"abstract":"<div><div>Mitochondrial dysfunction in renal tubular epithelial cells (TECs) is a hallmark of diabetic kidney disease (DKD), accompanied by macrophage infiltration, yet how metabolic perturbations in TECs-macrophage driven inflammation remains unclear. Here, we identify 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, as a critical mediator linking tubular mitochondrial stress to macrophage M1 polarization in DKD. In mice subjected to DKD, conditional knockout HMGCS2 in TECs decreases mitochondrial fission of TECs, M1 macrophage infiltration and tubular inflammatory injury. Combining LC-MS/MS and ketone flux detection reveals that desuccinylated HMGCS2 produced more acetoacetate (AcAc) than beta-hydroxybutyrate (β-HB) in TECs of DKD. Mechanistically, Signal Transducer and Activator of Transcription 3 (STAT3) promotes <em>Hmgcs2</em> transcription and sirtuin 5 (SIRT5) activates HMGCS2 through lysine desuccinylation at K367, which promotes AcAc overload shuttling from TECs to macrophages. AcAc acts as a signaling metabolite to activate the MIF/ERK pathway, driving M1 polarization and amplifying a pro-inflammatory feedback loop of tubular injury. In addition, AAV9-mediated <em>Hmgcs2</em> silencing therapy improves tubular inflammatory injury and attenuates DKD progression. Taken together, this study unveils a tubule-macrophage metabolic crosstalk axis mediated by HMGCS2-driven AcAc accumulation, which couples mitochondrial stress to immune response in DKD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156510"},"PeriodicalIF":11.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035399","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":"Essential role of endothelial T-cadherin in the transcytosis of circulating high-molecular-weight adiponectin to sub-vascular tissues","authors":"Shunsuke Shiode ,&nbsp;Yuya Fujishima ,&nbsp;Keita Fukuoka ,&nbsp;Saito Inoue ,&nbsp;Atsuya Shirono ,&nbsp;Keisuke Sirakura ,&nbsp;Yoshiaki Okada ,&nbsp;Yoshihisa Koyama ,&nbsp;Yuta Kondo ,&nbsp;Kohei Fujii ,&nbsp;Keitaro Kawada ,&nbsp;Hirofumi Nagao ,&nbsp;Yoshinari Obata ,&nbsp;Shiro Fukuda ,&nbsp;Shunbun Kita ,&nbsp;Shoichi Shimada ,&nbsp;Norikazu Maeda ,&nbsp;Hitoshi Nishizawa ,&nbsp;Iichiro Shimomura","doi":"10.1016/j.metabol.2025.156488","DOIUrl":"10.1016/j.metabol.2025.156488","url":null,"abstract":"<div><h3>Background</h3><div>Adiponectin, an adipocyte-derived protein, has diverse organ-protective effects, which are associated with its accumulation in vascular endothelial cells (VECs) as well as in various extravascular cell types, including skeletal muscle cells and cardiomyocytes. T-cadherin, a high-affinity binding partner for multimeric adiponectin, facilitates this accumulation; however, the mechanism by which high-molecular-weight (HMW) adiponectin transverses the endothelium remains unclear.</div></div><div><h3>Method and results</h3><div>We showed that tamoxifen-induced T-cadherin deficiency in VECs alone significantly increased plasma adiponectin levels, similar to inducible systemic T-cadherin deletion. The intravenous administration of adiponectin to adiponectin-deficient VEC-specific T-cadherin knockout mice markedly impaired the clearance of intravenously injected adiponectin, resulting in significant reductions in the accumulation of hexameric and HMW adiponectin, particularly the octadecameric (18-mer) form, not only in VECs, to note, but also in skeletal muscle and heart tissues. Furthermore, endothelial T-cadherin deficiency led to activation of innate immune signaling and cardiac remodeling, even under physiological conditions. In vitro experiments using MDCK II cells demonstrated that T-cadherin mediated the apical–to–basolateral transport of 18-mer adiponectin, largely preserving its HMW form. Additionally, intracellular adiponectin colocalized with the recycling endosome marker RAB11, and Rab11 deficiency significantly impaired its transcytosis. Similarly, in human VECs, T-cadherin knockdown significantly reduced basolateral adiponectin transport.</div></div><div><h3>Conclusions</h3><div>These findings identify vascular endothelial T-cadherin as a key mediator of HMW adiponectin transcytosis via the recycling endosome pathway, enabling its traversal from the circulation to sub-vascular tissues/cells and offering a mechanistic basis for the systemic organ-protective effects of adiponectin.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156488"},"PeriodicalIF":11.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903962","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":"Proteomic effects of short-term liraglutide vs. placebo in a blinded crossover RCT: Implications for efficacy, safety, and comparison with semaglutide","authors":"Konstantinos Stefanakis ,&nbsp;Valeria Gutierrez de Piñeres ,&nbsp;Preethi Veeragandham ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2026.156493","DOIUrl":"10.1016/j.metabol.2026.156493","url":null,"abstract":"<div><h3>Background</h3><div>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert cardiometabolic benefits beyond weight loss, yet their systemic proteomic mechanisms remain incompletely defined. We profiled short-term liraglutide-induced protein changes and compared them with published semaglutide signatures.</div></div><div><h3>Methods</h3><div>In a randomized, double-blind, placebo-controlled, crossover trial (<span><span>NCT02944500</span><svg><path></path></svg></span>), 20 adults with obesity received liraglutide 3 mg daily or placebo for 5 weeks, separated by a 3-week washout. Plasma and serum samples underwent SomaScan v4.1 profiling of 6249 proteins. Mixed-effects models tested Time×Treatment interactions with and without weight adjustment. Results were benchmarked against the 30-protein semaglutide STEP 1/2 signature.</div></div><div><h3>Results</h3><div>Liraglutide significantly modulated 124 proteins (57 FDR &lt; 0.05); 85 % of effects persisted after weight adjustment, indicating largely weight-independent actions. Upregulated proteins included pancreatic enzymes (PNLIP, CTRB1/2, PRSS2), while endothelial and fibrotic markers (ACE, NOS3, FAP) were downregulated. Myostatin (MSTN) was strongly suppressed (log₂ fold change −0.41; <em>p</em> = 1.7 × 10⁻⁶), with concurrent rises in its inhibitors WFIKKN2 and BMPR1A. Liraglutide shared 70–75 % directional overlap with semaglutide, with 25–30 % unique effects enriched in vascular, neurodevelopmental, and musculoskeletal pathways. A semaglutide-based classifier distinguished liraglutide from placebo (AUC = 0.82; sensitivity 0.89; specificity 0.60). Downregulated proteins were genetically linked to coronary artery disease and type 2 diabetes (FDR &lt; 0.05).</div></div><div><h3>Conclusions/interpretation</h3><div>Short-term liraglutide reproduces the core GLP-1RA proteomic fingerprint while uniquely suppressing myostatin and vascular remodeling pathways. These rapid, largely weight-independent molecular responses indicate early cardioprotective and myostatin-inhibitor signaling changes that could be relevant for future muscle-preserving strategies, supporting individualized GLP-1RA use beyond weight loss alone.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156493"},"PeriodicalIF":11.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145945045","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":"Multi-omics profiling reveals CKM syndrome severity as a gradient risk factor for cancer: A prospective cohort study","authors":"Yu Huang ,&nbsp;Yiwei Zhang ,&nbsp;Yanjun Zhang ,&nbsp;Ziliang Ye ,&nbsp;Sisi Yang ,&nbsp;Xiaoqin Gan ,&nbsp;Yiting Wu ,&nbsp;Yuanyuan Zhang ,&nbsp;Xianhui Qin","doi":"10.1016/j.metabol.2026.156508","DOIUrl":"10.1016/j.metabol.2026.156508","url":null,"abstract":"<div><h3>Objective</h3><div>Cardiovascular-Kidney-Metabolic (CKM) syndrome, a multisystem disorder, has been linked to cardiovascular and metabolic morbidity, but its association with cancer risk remains poorly characterized. This study aimed to examine the relationship between CKM syndrome severity and the incidence of overall cancer and 18 site-specific cancers, and to identify potential mediating plasma protein and metabolite signatures.</div></div><div><h3>Methods</h3><div>We analyzed data from 351,239 participants in the UK Biobank, classified into five CKM syndrome stages (0–4). Plasma proteomic (2923 proteins) and metabolomic (168 metabolites) profiles were analyzed. Cox models evaluated associations, and mediation analyses identified biological mediators.</div></div><div><h3>Results</h3><div>Over a median 13.5-year follow-up, 44,840 incident cancer cases were documented. Advancing CKM stages (0–3) showed a dose-response relationship with increased overall (per one-stage increase: adjusted HR, 1.05; 95%CI, 1.03–1.07) and eleven site-specific cancer risks (e.g., digestive, respiratory, urinary tracts) (per one-stage increase: adjusted HR ranging from 1.06 to 1.46). Stage 4 remained associated with elevated risk, though attenuated versus stage 3. Multi-omics mediation analysis identified 22 proteins and 2 metabolites that partially mediated the association between CKM stages 0–3 and overall cancer risk, implicating immune and metabolic pathways. Functional enrichment analysis further highlighted the PI3K-Akt signaling pathway and inflammatory processes as key mechanistic contributors.</div></div><div><h3>Conclusions</h3><div>CKM syndrome severity is independently associated with increased cancer risk, partially mediated by proteins and metabolites involved in inflammation, proliferation, and lipid metabolism. These findings support CKM staging as a multisystem disorder with significant oncological implications and highlight potential biomarkers for intervention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156508"},"PeriodicalIF":11.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990003","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":"CADD-engineered peptide protacs efficiently target PCSK9 for hypercholesterolemia in vivo","authors":"Gang Fan ,&nbsp;Weiming Guo ,&nbsp;Jingfen Lu ,&nbsp;Yaohui He ,&nbsp;Jinhui Zha ,&nbsp;Qingping Zhang ,&nbsp;Yuling Chen ,&nbsp;Dong Tan ,&nbsp;Zhihan Tang ,&nbsp;Jing Yang ,&nbsp;Zhijian Yu ,&nbsp;Miao Liu","doi":"10.1016/j.metabol.2025.156485","DOIUrl":"10.1016/j.metabol.2025.156485","url":null,"abstract":"<div><h3>Background</h3><div>Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein receptors (LDLR), leading to elevated plasma LDL cholesterol (LDL-C) and increased risk of hypercholesterolemia. Current therapeutic approaches, such as monoclonal antibodies and gene-editing tools, face significant challenges including high cost, safety issues, and limited ability to target intracellular PCSK9.</div></div><div><h3>Methods</h3><div>Using computer-aided drug design (CADD), we developed Cadd4, a novel peptide-based degrader targeting PCSK9. Molecular docking was employed to identify a high-affinity peptide sequence, which was then validated through in vitro studies using LX-2 cells and in vivo experiments in high-fat diet (HFD)-induced hypercholesterolemic mice. Biodistribution and toxicity assessments were performed to evaluate tissue specificity and safety. Human liver tissue experiments were conducted to assess translational efficacy.</div></div><div><h3>Results</h3><div>Cadd4 exhibited efficient intracellular uptake and significantly reduced PCSK9 levels, resulting in upregulated LDLR expression. In HFD-fed mice, hepatic PCSK9 was decreased by 38 %, accompanied by a 25 % reduction in total cholesterol and a 29 % reduction in LDL-C. Biodistribution analysis revealed liver-specific accumulation with no signs of systemic toxicity. In human liver tissues, Cadd4 effectively degraded PCSK9 and restored LDLR expression. Compared with the clinical-stage PCSK9 inhibitor, Cadd4 demonstrated promising lipid-lowering efficacy and the potential for a longer duration of action.</div></div><div><h3>Conclusion</h3><div>Cadd4 represents a promising CADD-designed therapeutic strategy for cholesterol management by targeting intracellular PCSK9 for degradation. This approach overcomes key limitations of existing therapies and underscores the potential of targeted protein degradation in cardiovascular disease treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156485"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834402","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":"TRP channels at the crossroads of metabolism and immunity: ion–metabolite coupling in inflammation and disease","authors":"De-Hua Liao ,&nbsp;Shi-Long Jiang ,&nbsp;Ting Wu ,&nbsp;Zeng Cao ,&nbsp;Ze-Wu Zhu ,&nbsp;Nayiyuan Wu ,&nbsp;Xiu Zhang ,&nbsp;Ming-Hui Long ,&nbsp;Jing Wang ,&nbsp;Zhi-Bin Wang","doi":"10.1016/j.metabol.2025.156486","DOIUrl":"10.1016/j.metabol.2025.156486","url":null,"abstract":"<div><div>Transient receptor potential (TRP) channels are not only multimodal ion sensors but also couplers between metabolic states and immune responses. TRP gating is controlled by lipid signaling (PIP2, DAG, cholesterol), redox/energy cues (NAD⁺/ADPR/ROS, ATP/AMP), and metabolite-derived signals (pH/lactate, bile acids, endocannabinoids, eicosanoids, SCFAs). In turn, TRP-driven Ca²⁺ signaling reprograms AMPK–mTORC1, glycolysis/OXPHOS, FAO, and glutaminolysis, thereby reshaping the metabolic programs and effector functions of T/B cells, macrophages, NK/DCs. In gut, skin, and arthritis, microbiota–metabolite–TRP axes dictate inflammatory phenotypes; within tumors, lactate, adenosine, and kynurenine modulate TRPs in cancer and immune infiltrates. In this study, we synthesize TRP metabolic sensing mechanisms, immunometabolic reprogramming, and pharmacological opportunities, highlighting synergistic strategies combining metabolic interventions with TRP modulation for precision management of inflammation-related diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156486"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878710","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":"Incretin-based therapy and atrial fibrillation risk in overweight or obesity","authors":"Paschalis Karakasis ,&nbsp;Konstantinos Vlachos ,&nbsp;Nikolaos Fragakis ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2025.156491","DOIUrl":"10.1016/j.metabol.2025.156491","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156491"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888879","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":"The SEMA7AN559Y mutation facilitates the development of metabolic dysfunction-associated steatotic liver disease by inducing ROS/NLRP3-mediated hepatic cell pyroptosis","authors":"Xiaoxun Zhang ,&nbsp;Jiaxin Lei ,&nbsp;Nan Zhao ,&nbsp;Zhixian Zhu ,&nbsp;Jingjing Ding ,&nbsp;Qiong Pan ,&nbsp;Wen-Yue Liu ,&nbsp;Xiao-Zhi Jin ,&nbsp;Li-You Lian ,&nbsp;Ming-Hua Zheng ,&nbsp;Jin Chai","doi":"10.1016/j.metabol.2025.156483","DOIUrl":"10.1016/j.metabol.2025.156483","url":null,"abstract":"<div><h3>Background and aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver condition that can result in significant liver damage. This study aimed to evaluate the effects of the <em>SEMA7A</em>^N559Y mutation on MASLD progression and to explore potential therapeutic targets.</div></div><div><h3>Methods</h3><div>To examine the impact of the <em>SEMA7A</em>^N559Y mutation on MASLD progression, we generated <em>Sema7a</em>^N557Y (equal to human <em>SEMA7A</em>^N559Y) heterozygous mutant mice. At 8 weeks old, both wild-type and <em>Sema7a</em>^N557Y heterozygous mice were placed on a high-fat diet. After dietary intervention, mice were euthanized, and serum and liver tissues were collected for analysis. The effects of the <em>SEMA7A</em>^N559Y mutation on MASLD progression were assessed using biochemical assays, histological analysis, and Western blotting.</div></div><div><h3>Results</h3><div>The <em>Sema7a</em>^N557Y mutation worsened lipid metabolism disorders, causing hepatic steatosis, inflammation, and fibrosis in mice fed a high-fat diet. The <em>SEMA7A</em>^N559Y mutation strengthens its interaction with integrin β1, triggering the PI3K/Akt pathway and increasing ROS production, which leads to hepatic oxidative stress and NLRP3 inflammasome activation.</div></div><div><h3>Conclusion</h3><div>The N559Y variant in SEMA7A suggests a potential association with exacerbated hepatic oxidative stress, heightened pyroptosis, and increased MASLD severity. Targeting the SEMA7A-integrin β1 interaction could represent a potential novel therapeutic approach.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156483"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810603","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":"Consensus statement on vitamin D role in metabolic health","authors":"Andrea Giustina ,&nbsp;Luigi di Filippo ,&nbsp;Aneta Aleksova ,&nbsp;Jens Bollerslev ,&nbsp;Anna Maria Colao ,&nbsp;Bess Dawson-Hughes ,&nbsp;Lorenzo M. Donini ,&nbsp;Peter R. Ebeling ,&nbsp;Marise Lazaretti-Castro ,&nbsp;Roberto Lorusso ,&nbsp;Livio Luzi ,&nbsp;Claudio Marcocci ,&nbsp;Salvatore Minisola ,&nbsp;Nicola Napoli ,&nbsp;Anastassios G. Pittas ,&nbsp;René Rizzoli ,&nbsp;Patrizia Rovere Querini ,&nbsp;Ferruccio Santini ,&nbsp;Anne L. Schafer ,&nbsp;Jyrki K. Virtanen ,&nbsp;John P. Bilezikian","doi":"10.1016/j.metabol.2025.156484","DOIUrl":"10.1016/j.metabol.2025.156484","url":null,"abstract":"<div><div>The 8th International Conference Controversies in Vitamin D, held in September 2024, convened leading experts to address the multifaceted role of vitamin D in human health. Key discussions focused on its influence on metabolic health, including effects on sarcopenia, muscle function, and energy metabolism, as well as its role in obesity, cardiovascular health, and diabetes. Preclinical evidence was presented, suggesting a pivotal role of vitamin D in regulating muscle function and repair, potentially preventing sarcopenia. A relationship between low vitamin D (25[OH]D) concentrations and increased risk of cardiovascular diseases and diabetes was supported by several preclinical and clinical studies. Vitamin D supplementation was recently demonstrated to help improve glycemia and reduce the progression to diabetes and increase the likelihood of regression to normal glucose regulation in adults with prediabetes. Despite mixed outcomes from large, population-based randomized clinical trials, the conference underscored the critical need for personalized research, through disease-specific clinical trials, to fully elucidate the therapeutic potential of vitamin D supplementation, particularly in chronic conditions such as cardiovascular diseases and diabetes. In conclusion, while vitamin D demonstrates considerable promise in modifying a wide array of metabolic health concerns, rigorous scientific inquiry is essential to deepen our understanding of its mechanisms as well as potential protective effects and establish evidence-based guidelines for supplementation. This growing body of work has the potential to significantly enhance clinical outcomes and improve public health strategies, calling for continued exploration and collaboration in the field of vitamin D research.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156484"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820209","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":"Meteorin-like protein inhibits vascular smooth muscle cell-derived foam cell formation and atherosclerosis via KIT- endoplasmic reticulum stress signaling","authors":"Xu Chen ,&nbsp;Xueying Jiang ,&nbsp;Siyu Hou ,&nbsp;Fengling Lai ,&nbsp;Keqing Hu ,&nbsp;Jie Li ,&nbsp;Ting Yang ,&nbsp;Xinxin Shen ,&nbsp;Huimin Chen ,&nbsp;Shen Chen ,&nbsp;Xianfei Guo ,&nbsp;Yan Zheng ,&nbsp;Tao Xu ,&nbsp;Guohai Su ,&nbsp;Rong Huang","doi":"10.1016/j.metabol.2025.156459","DOIUrl":"10.1016/j.metabol.2025.156459","url":null,"abstract":"<div><h3>Objective</h3><div>Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known metabolic and anti-inflammatory effects, has been linked to cardiovascular protection, but its role in atherosclerosis is not well defined. This study investigated the function of METRNL in VSMC-derived foam cell formation and atherosclerosis and explored the underlying signaling mechanisms.</div></div><div><h3>Methods</h3><div>ApoE^−/− mice were used to investigate the role of METRNL in atherosclerosis. VSMC-derived foam cell formation was evaluated in human VSMC treated with oxidized LDL with or without METRNL supplementation.</div></div><div><h3>Results</h3><div>METRNL levels declined during atherosclerosis progression and were restored during regression. METRNL selectively inhibited foam cell formation in VSMCs—but not in macrophages—by downregulating CD36-mediated cholesterol uptake and suppressing endoplasmic reticulum stress through KIT signaling. Deletion of KIT specifically in smooth muscle cells abolished these protective effects. The transcription factor SP1 was found to bind directly to the METRNL promoter and enhance its expression. Clinically, lower serum METRNL levels were independently associated with increased risk and severity of acute coronary syndrome.</div></div><div><h3>Conclusion</h3><div>METRNL protects against VSMC foam cell formation and atherosclerosis by enhancing KIT signaling, thereby reducing ER stress and subsequent cholesterol uptake. These findings position METRNL as a potential therapeutic target and biomarker for atherosclerotic cardiovascular disease.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156459"},"PeriodicalIF":11.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653290","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}