Metabolism: clinical and experimental最新文献

{"title":"MINDY1 drives metabolic-immune crosstalk via OGT-UGP2-UDPG axis to promote immunosuppressive macrophage reprogramming.","authors":"Kejing Zhang, Kui Chen, Xinyu Mi, Yilin Pan, Desheng Xiao, Shuang Liu, Ledu Zhou, Yongguang Tao, Jing Cao, Jianing Tang","doi":"10.1016/j.metabol.2026.156795","DOIUrl":"https://doi.org/10.1016/j.metabol.2026.156795","url":null,"abstract":"<p><p>The efficacy of immune checkpoint blockade is limited in hepatocellular carcinoma (HCC) due to tumor-intrinsic mechanisms. Here we identify the deubiquitinase MINDY1 as a central regulator of metabolic-immune crosstalk that drives immunotherapy resistance in HCC. MINDY1 is significantly upregulated in immunotherapy non-responders and correlates with poor prognosis and increased M2-like macrophage infiltration. Mechanistically, MINDY1 stabilizes O-GlcNAc transferase (OGT) by removing K48-linked ubiquitin chains, thereby enhancing O-GlcNAcylation of uridine diphosphate glucose pyrophosphorylase 2 (UGP2) at T152. This modification promotes UGP2 enzymatic activity and increases uridine diphosphate glucose (UDPG) synthesis and extracellular accumulation. Tumor-derived UDPG acts as an extracellular immunometabolite that directly binds to PPARγ in macrophages, promoting its nuclear translocation and transcriptional activation. UDPG-driven PPARγ signaling enhances fatty acid oxidation and induces M2-like polarization, suppressing CD8⁺ T-cell cytotoxicity and establishing an immunosuppressive tumor microenvironment. Targeting MINDY1 remodels macrophage metabolism, restores CD8⁺ T-cell effector function, and significantly enhances anti-PD-1 efficacy in vivo. Our findings uncover a previously unrecognized mechanism that links tumor proteostasis to immune suppression and identify MINDY1 as a promising therapeutic target for overcoming immunotherapy resistance in HCC.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156795"},"PeriodicalIF":16.7,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112097","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":"Adipocyte caspase-1 deficiency promotes white fat beiging via COX7A2L-dependent mitochondrial respiration.","authors":"Yumeng Wang, Jiajie Li, Weijiong He, Furong Zhao, Yunzi Kang, Yewei Cui, Hongxiang Zeng, Ting Zeng, Rui Cheng, Shujin Wang, Linqiang Zhang, Rui Wang, Xueya Zhao, Liuling Xiao, Xi Li","doi":"10.1016/j.metabol.2026.156729","DOIUrl":"10.1016/j.metabol.2026.156729","url":null,"abstract":"<p><p>Beiging of white adipose tissue (WAT) is a promising strategy to enhance energy expenditure and combat obesity, a growing global health burden. Here, we identify a non-canonical role of caspase-1, a cysteine protease, in regulating adipocyte thermogenesis. Caspase-1 expression in adipocytes of inguinal WAT is downregulated upon cold exposure but elevated in obesity. Adipocyte-specific caspase-1 deficiency promotes WAT beiging, increases whole-body energy expenditure, and ameliorates high-fat diet-induced obesity and metabolic dysfunction. Mechanistically, cAMP signaling suppresses Casp1 transcription via C/EBPβ. Proteomic and functional analyses reveal that caspase-1 interacts with and modulates the protein levels of COX7A2L, a subunit of mitochondrial complex IV. Loss of Casp1 stabilizes COX7A2L, thereby enhancing mitochondrial respiration. Moreover, CASP1 expression in human WAT significantly increases with obesity and metabolic dysfunction. Accordingly, we developed a sustained-release delivery system for the caspase-1 inhibitor Ac-YVAD-CHO, which effectively protects against diet-induced obesity and improves glucose tolerance in mice. These findings reveal a previously unrecognized inflammation-independent role of adipocyte-intrinsic caspase-1 in adipose beiging and highlight caspase-1 as a potential therapeutic target for obesity.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156729"},"PeriodicalIF":16.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679396","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":"Letter to the editor: Short siesta habit and cardiometabolic health: A 7-year follow-up in coronary heart disease patients from the CORDIOPREV study.","authors":"Jiayan Qu, Rong Yao, Jingbo Lu","doi":"10.1016/j.metabol.2026.156784","DOIUrl":"10.1016/j.metabol.2026.156784","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156784"},"PeriodicalIF":16.7,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081501","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":"Short siestas or healthier nappers? Interpreting seven-year cardiometabolic associations in coronary heart disease: Letter to the editor.","authors":"Jinyun Wang, Zhong Wang","doi":"10.1016/j.metabol.2026.156775","DOIUrl":"10.1016/j.metabol.2026.156775","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156775"},"PeriodicalIF":16.7,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062834","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":"Tissue compartment limits the apparent late-stage decline in hepatic ENT1.","authors":"Feiqi Xu, Lei Jin","doi":"10.1016/j.metabol.2026.156771","DOIUrl":"10.1016/j.metabol.2026.156771","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156771"},"PeriodicalIF":16.7,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062773","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":"Short siesta and cardiometabolic health in coronary heart disease: Independent effect or marker of a broader behavioral phenotype?","authors":"Enjing Zhang, Peng Zhou","doi":"10.1016/j.metabol.2026.156783","DOIUrl":"10.1016/j.metabol.2026.156783","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156783"},"PeriodicalIF":16.7,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030911","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":"Response to \"Tissue compartment limits the apparent late-stage decline in hepatic ENT1\".","authors":"Aida Mata-Ventosa, Sandra Pérez-Torras","doi":"10.1016/j.metabol.2026.156780","DOIUrl":"10.1016/j.metabol.2026.156780","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156780"},"PeriodicalIF":16.7,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990663","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":"Habitual siesta patterns and cardiometabolic trajectories: Response to Wang and Wang.","authors":"Marta Garaulet, Juan Luis Romero-Cabrera, Antonio García-Ríos, José López-Miranda","doi":"10.1016/j.metabol.2026.156776","DOIUrl":"10.1016/j.metabol.2026.156776","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156776"},"PeriodicalIF":16.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977239","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":"PFKFB3 nuclear translocation improves diabetic retinopathy by attenuating endothelial cell senescence through inhibition of USP7-p53 axis","authors":"Peiyu Liu ,&nbsp;Ning Shen ,&nbsp;Yali Zhou ,&nbsp;Jingyi Wu ,&nbsp;Meng Hao ,&nbsp;Shuchang Zhang ,&nbsp;Yifan Wang ,&nbsp;Xiaoqian Wang ,&nbsp;Huiming Li ,&nbsp;Zhipeng You ,&nbsp;Huimin Fan ,&nbsp;Xun Xu ,&nbsp;Ning Wang ,&nbsp;Dandan Sun ,&nbsp;Fang Wei","doi":"10.1016/j.metabol.2026.156553","DOIUrl":"10.1016/j.metabol.2026.156553","url":null,"abstract":"<div><h3>Background</h3><div>Endothelial cell (EC) senescence is a key contributor to retinal vascular dysfunction in diabetic retinopathy (DR), yet its molecular mechanisms remain incompletely understood. While PFKFB3 is well recognized for its critical function in modulating EC glycolysis and angiogenesis, its contribution to endothelial senescence in DR has not been elucidated.</div></div><div><h3>Methods</h3><div>Single-cell RNA sequencing was used to profile EC senescence signatures and barrier/tight-junction programs in diabetic retinas. PFKFB3/USP7 abundance and senescence in vivo and in vitro were assessed by Western blotting, SA-β-gal staining, immunofluorescence, and cell-cycle flow cytometry. PFKFB3-USP7 interaction was examined by co-immunoprecipitation, mass spectrometry, and nuclear colocalization. Retinal vascular dysfunction was quantified by Evans blue leakage and PAS-stained retinal trypsin digests.</div></div><div><h3>Results</h3><div>Single-cell analysis identified EC subclusters enriched for senescence transcripts and simultaneously depleted for barrier/tight-junction pathways in diabetic retinas. Hyperglycemia reduced PFKFB3 and impaired its nuclear entry, leading to prominent cellular senescence in vitro and in vivo, and restoration of PFKFB3 effectively reversed this phenotype. By establishing stable endothelial cell lines expressing PFKFB3 only in the nucleus (NLS mutant) or cytoplasm (K472Q mutant), we revealed that anti-senescent activity required PFKFB3 nuclear localization. Nuclear-localized PFKFB3 interacted with USP7, a critical modulator of the p53 pathway, and regulated the USP7-p53 axis by constraining their coupling, thereby promoting proteasomal degradation of p53. As a downstream effector of PFKFB3, USP7 abrogated the protective effect of PFKFB3, whereas its inhibition attenuated hyperglycemia-induced senescence and mitigated retinal vascular dysfunction.</div></div><div><h3>Conclusions</h3><div>Our findings highlighted the essential role of nuclear PFKFB3 dysfunction and USP7-p53 axis dysregulation in mediating EC senescence under diabetic stress, suggesting that targeting PFKFB3 nuclear translocation may be a novel therapeutic strategy for the prevention of diabetic retinopathy.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"178 ","pages":"Article 156553"},"PeriodicalIF":11.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142945","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":"Enduring improvements in hepatic insulin sensitivity predict sustained remission of prediabetes during a 3-year lifestyle intervention: results from the PREVIEW multinational diabetes prevention trial","authors":"Ruixin Zhu ,&nbsp;Jie Guo ,&nbsp;Maija Huttunen-Lenz ,&nbsp;Gareth Stratton ,&nbsp;Nils Swindell ,&nbsp;Ian A. Macdonald ,&nbsp;Teodora Handjieva-Darlenska ,&nbsp;Svetoslav Handjiev ,&nbsp;Santiago Navas-Carretero ,&nbsp;Sally D. Poppitt ,&nbsp;Marta Silvestre ,&nbsp;Wolfgang Schlicht ,&nbsp;Mikael Fogelholm ,&nbsp;J. Alfredo Martinez ,&nbsp;Anne Raben ,&nbsp;Jennie Brand-Miller","doi":"10.1016/j.metabol.2026.156546","DOIUrl":"10.1016/j.metabol.2026.156546","url":null,"abstract":"<div><h3>Background</h3><div>Recent investigation advocates the use of prediabetes remission as a goal of diabetes prevention. We aimed to compare changes in metabolic markers in participants with and without sustained remission of prediabetes during a 3-year lifestyle intervention.</div></div><div><h3>Methods</h3><div>This <em>post-hoc</em> analysis used data from the PREVIEW trial, a 3-year, multinational, multicenter, randomized controlled trial aiming to examine the effects of lifestyle interventions on prevention of type 2 diabetes among high-risk adults. Adult participants with prediabetes and overweight/obesity underwent 8-weeks of rapid weight loss followed by a 148-week lifestyle intervention for weight loss maintenance. Participants who completed the full protocol and had available data (<em>n</em> = 846) were included in the current analysis. Participants were classified into prediabetes maintainers, relapsers, and non-responders according to blood glucose levels at 1 and 3 years. Changes in metabolic markers over 3 years were compared in those who achieved sustained remission (maintainers, <em>n</em> = 102) vs those who failed (non-responders, <em>n</em> = 618), as well as those who were successful at 1 year but then relapsed (relapsers, <em>n</em> = 126).</div></div><div><h3>Results</h3><div>Only 12% participants experienced sustained remission at 3 years. After adjusting for baseline covariates, compared with non-responders, maintainers achieved greater weight loss (mean difference −4.0 kg; 95% CI −5.8, −2.2 kg) and fat mass loss at 3 years. Maintainers also made further improvements in markers of hepatic insulin sensitivity, regardless of weight change. Compared with relapsers, maintainers had greater decreases in weight and fat mass, but changes in visceral adiposity index were similar. Relapsers gradually reverted to an insulin resistant state at 2 and 3 years compared with maintainers, independent of weight change.</div></div><div><h3>Conclusions</h3><div>In a long-term lifestyle intervention, sustained remission of prediabetes was associated with enduring improvements in hepatic insulin sensitivity, regardless of weight change. In addition to weight loss, targeting hepatic insulin sensitivity per se may help prevent relapse in prediabetes.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"178 ","pages":"Article 156546"},"PeriodicalIF":11.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135657","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}