Metabolism: clinical and experimental最新文献

{"title":"Chemical discovery of a novel MD2/ADAM17 dual-target inhibitor as a potential therapeutic candidate for saturated fatty acid-induced myocardial inflammatory injury","authors":"Xiao-dan Zhang ,&nbsp;Yun-shan Zhong ,&nbsp;Hao Yan ,&nbsp;Le-hao Jin ,&nbsp;Jing Chen ,&nbsp;Zhong-xi Chen ,&nbsp;Zhe-yan Zhang ,&nbsp;Yun-jie Zhao ,&nbsp;Jian-chang Qian","doi":"10.1016/j.metabol.2025.156298","DOIUrl":"10.1016/j.metabol.2025.156298","url":null,"abstract":"<div><h3>Background and aims</h3><div>While the therapeutic promise of anti-inflammatory interventions for obesity-associated cardiomyopathy is well recognized, clinically effective targeted therapies remain to be developed. Here, through systematic anti-inflammatory screening, we elucidated both the therapeutic efficacy and mechanistic basis of a novel indole-substituted acetamide derivative (compound #3) in mitigating obesity-induced cardiomyopathy.</div></div><div><h3>Methods</h3><div>A high-fat diet (HFD)-induced obese mouse model was used to evaluate the cardioprotective efficacy of compound #3. Integrated <em>in vivo</em> and <em>in vitro</em> studies, including transcriptomics, reverse molecular docking, proteomics, surface plasmon resonance, and kinase activity assays, were conducted to systematically identify molecular targets and elucidate the underlying mechanisms.</div></div><div><h3>Results</h3><div>Compound #3 attenuated hypertension in HFD-induced obese mice without altering metabolic parameters (body weight, blood glucose, and lipid levels). This cardioprotective effect was attributed to improved cardiac function and anti-inflammatory mechanisms, including the suppression of NF-κB-driven inflammatory injury. Mechanistic studies revealed that compound #3 targeted the L348 residue of ADAM17, disrupting ADAM17-dependent inflammatory signal amplification. This cascade was primarily initiated by the MD2-P38MAPK/JNK-iRhom2 axis. In addition, compound #3 directly bound to MD2, inhibiting palmitic acid (PA)-induced activation of P38MAPK and JNK. This mechanism blocked the initiation of inflammatory responses and further suppressed ADAM17 and cytokine transcription through the P38MAPK-AP1 axis.</div></div><div><h3>Conclusion</h3><div>Compound #3 exhibits a dual-targeting mechanism by simultaneously inhibiting MD2 and ADAM17, which effectively suppresses both the initiation (via the MD2-P38MAPK/JNK) and amplification (via the P38MAPK/JNK-iRhom2-ADAM17 axis) of inflammatory cascades, highlighting its strong therapeutic promise for treating saturated fatty acid-induced myocardial pathologies.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156298"},"PeriodicalIF":10.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094362","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":"Use of finerenone in patients with chronic kidney disease at high risk of heart failure","authors":"John P. Hakim ,&nbsp;Yehuda Handelsman ,&nbsp;Trina Banerjee","doi":"10.1016/j.metabol.2025.156297","DOIUrl":"10.1016/j.metabol.2025.156297","url":null,"abstract":"<div><div>Treatment of symptomatic/advanced heart failure (HF) in patients who also have chronic kidney disease (CKD) and type 2 diabetes (T2D) may include a steroidal mineralocorticoid receptor antagonist (MRA). However, patients with CKD and T2D who are at high risk of developing HF may benefit from taking the nonsteroidal MRA finerenone. Results from phase 3 placebo-controlled trials of finerenone in patients with CKD associated with T2D showed that finerenone (plus a renin-angiotensin-aldosterone system inhibitor) reduced the risk of new-onset HF, improved other HF outcomes, and caused a significant slowing of CKD progression. Those who work in cardiology need to be aware of the HF risk-reduction effects of finerenone in patients with CKD and T2D. In this review, we provide a rationale for finerenone use in cardiology based on the available finerenone clinical trial data and from the perspective of a cardiologist who prescribes finerenone to patients who have comorbid CKD and T2D.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156297"},"PeriodicalIF":10.8,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069996","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":"Evaluation of tetrahydropyridazine-based peripherally restricted dual inhibitors of CB1R and inducible nitric oxide synthase (iNOS) for treating metabolic syndrome disorders","authors":"Pinaki Bhattacharjee ,&nbsp;Szabolcs Dvorácskó ,&nbsp;Océane Pointeau ,&nbsp;Biswajit Kundu ,&nbsp;Nicholas Rutland ,&nbsp;Henry Puhl III ,&nbsp;Jie Liu ,&nbsp;Grzegorz Godlewski ,&nbsp;Sergio A. Hassan ,&nbsp;Tony Jourdan ,&nbsp;Resat Cinar ,&nbsp;Malliga R. Iyer","doi":"10.1016/j.metabol.2025.156291","DOIUrl":"10.1016/j.metabol.2025.156291","url":null,"abstract":"<div><h3>Background and purpose</h3><div>The endocannabinoid system is a key regulator of metabolism, sparking interest in cannabinoid type 1 receptor (CB1R) antagonists as potential treatments for obesity and related conditions collectively called metabolic syndrome disorders. However, the neuropsychiatric liabilities associated with centrally acting CB1R antagonists led researchers to focus on developing peripherally restricted compounds that do not cross the blood-brain barrier (BBB).</div><div>This study aimed to synthesize and evaluate novel CB1R antagonists based on tetrahydropyridazine core incorporating physicochemical design principles that would allow for negligible BBB penetration. The efficacy of the compounds was assessed in rodent models of diet induced obesity and diabetes.</div></div><div><h3>Experimental approach</h3><div>In this study, we employed a rational-design approach along with structure-based modeling to develop small-molecule CB1R antagonists that are peripherally acting. Pharmacological profiles of two racemic compounds PB19A and PB95 were evaluated in cannabinoid receptor binding studies, and functional [³⁵S]-GTPγS assays. Further chiral separation of enantiomers allowed for the evaluation of respective eutomers in in vitro ADME studies along with in vivo pharmacokinetic and tissue distribution studies in mice. The results showed that the compounds are orally bioavailable and had negligible brain penetrance. The design features also incorporated putative amidine moieties which inhibit the pro-inflammatory enzyme; inducible nitric oxide synthase (iNOS). Both biochemical and in vitro cell-based assays showed the CB1R antagonists having iNOS inhibitor properties. In vivo CB1R functional antagonism was assessed by upper gastrointestinal motility assay. The efficacy of our CB1R antagonists was compared with brain penetrant ibipinabant in a diet-induced obesity mouse model, assessing effects on lipid metabolism biomarkers, food intake, body weight reduction, glucose tolerance and insulin resistance.</div></div><div><h3>Key results</h3><div>Novel compounds PB19AE2 and PB95E2 were designed and evaluated as peripherally restricted CB1R antagonists. In high fat diet fed mice, these compounds improved metabolic parameters, modestly reduced food intake, and ameliorated hepatic lipid metabolism markers.</div></div><div><h3>Conclusion and implications</h3><div>Overall, PB19AE2 and PB95E2 are orally bioavailable, peripherally acting CB1 antagonists and their preliminary evaluation show promising potential in utilizing the pyridazine-based compounds for generating potent leads for treating obesity- associated disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156291"},"PeriodicalIF":10.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079111","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":"Non-invasive diagnosis and prognosis of MASH with fibrosis F2-F3: In need for a tailored, accessible, and affordable solution for the 21st century public health epidemic","authors":"Konstantinos Stefanakis ,&nbsp;Jacob George ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2025.156296","DOIUrl":"10.1016/j.metabol.2025.156296","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156296"},"PeriodicalIF":10.8,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012867","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":"Reconsidering the role of active vitamin D in preventing sarcopenia: Letter to the editor","authors":"Xinxin Luo ,&nbsp;Juntong Liu ,&nbsp;Li Wang","doi":"10.1016/j.metabol.2025.156274","DOIUrl":"10.1016/j.metabol.2025.156274","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156274"},"PeriodicalIF":10.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972033","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 role of active vitamin D in preventing sarcopenia—Authors' reply","authors":"Tetsuya Kawahara ,&nbsp;Tetsuya Inazu ,&nbsp;Gen Suzuki","doi":"10.1016/j.metabol.2025.156293","DOIUrl":"10.1016/j.metabol.2025.156293","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156293"},"PeriodicalIF":10.8,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027931","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":"Targeting RBP4–STRA6 retinol signaling disrupts adipose–prostate crosstalk: A novel strategy to suppress basal cell plasticity in androgen deprivation","authors":"Huan Xu ,&nbsp;Dajun Gao ,&nbsp;Yanting Shen ,&nbsp;Jianqing Wang ,&nbsp;Junduo Wang ,&nbsp;Jun Zhu ,&nbsp;Miao Ren ,&nbsp;Lai Wei ,&nbsp;Hailiang Hu ,&nbsp;Ming Zhan ,&nbsp;Zhong Wang ,&nbsp;Fubo Wang ,&nbsp;Bin Xu","doi":"10.1016/j.metabol.2025.156288","DOIUrl":"10.1016/j.metabol.2025.156288","url":null,"abstract":"<div><div>Metabolic rewiring is a starter for lineage plasticity, which is an important driver of prostate development, tumorigenesis and treatment resistance. Androgen-targeted therapies are central to prostate cancer (PCa) management, yet the mechanisms leading prostate development—particularly the metabolic signaling within basal cells during treatment—remain poorly understood. To fulfill this gap, we used multiple models to reveal the metabolic alterations in prostate basal cells. Our study reveals the role of the RBP4-STRA6 axis in modulating retinol metabolism and transporting retinol from adipocyte into prostate cells, contributing to prostate development and basal cell differentiation during androgen deprivation. Through multi-omics analyses, we demonstrate that RBP4-STRA6 axis dependent retinol metabolism is increased with androgen deprivation. Retinol metabolism rewiring is modulated by the androgen receptor (AR) and can regulate basal cell plasticity under androgen deprivation therapy (ADT). Retinol metabolism maintains prostate basal cell lineage plasticity during hormone therapy through the PPARγ signaling pathway, compensating for the AR signaling pathway inhibition by sustaining energy homeostasis and promoting basal cell differentiation. Notably, we identified a basal cell cluster (BC5) characterized by high Retinol metabolism and activated PPARγ signaling pathway, which plays a crucial role in basal-luminal differentiation and prostate growth. This study underscores the importance of RBP4-STRA6 dependent Retinol metabolism, mediating the crosstalk between adipocytes and prostate basal cells, in maintaining prostate development during hormone therapy and provides a foundation for future clinical interventions and diet strategies aimed at enhancing the sensitivity of androgen deprivation in prostate diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156288"},"PeriodicalIF":10.8,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923914","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":"TBC1D15 protects alcohol-induced liver injury in female mice through PLIN5-mediated mitochondrial and lipid droplet contacting","authors":"Haixia Xu ,&nbsp;Jiayu Shi ,&nbsp;Wenjun Yu ,&nbsp;Shiqun Sun ,&nbsp;Haoxiong Zhou ,&nbsp;Lu Wang ,&nbsp;Jun Ren ,&nbsp;Zhifeng Gu ,&nbsp;Qi Lu ,&nbsp;Yingmei Zhang","doi":"10.1016/j.metabol.2025.156290","DOIUrl":"10.1016/j.metabol.2025.156290","url":null,"abstract":"<div><h3>Objective</h3><div>Alcohol-induced hepatic steatosis and mitochondrial dysfunction are progressive conditions contributing to the development of alcoholic liver disease (ALD), often leading to cirrhosis and hepatocellular carcinoma. TBC1D15, a Rab7 GTPase-activating protein (GAP), has been implicated in mitochondrial homeostasis, however, its role in ALD remains elusive. This study aimed to investigate the functional role of TBC1D15 in ALD and elucidate the underlying mechanisms.</div></div><div><h3>Methods</h3><div>Female TBC1D15^flox/flox mice and hepatocyte-specific overexpression of TBC1D15 mice were fed a Lieber-DeCarli ethanol diet, which progressively increasing ethanol dosages over 8 weeks. Liver tissues were assessed using histology, transmission electron microscopy, immunofluorescence, immunoblotting, and real-time PCR techniques.</div></div><div><h3>Results</h3><div>TBC1D15 levels were markedly decreased in human ALD samples and primary hepatocytes exposed to ethanol. Hepatocyte-specific TBC1D15 overexpression attenuated alcohol-induced body weight loss, improved survival, and alleviated liver injury, lipid droplet (LD) accumulation, and hepatocyte apoptosis. TBC1D15 overexpression also protected against alcohol-induced mitochondrial dysfunction and enhanced mitochondrial fatty acid β-oxidation (FAO) by promoting interactions between mitochondria and LDs in the face of alcohol exposure. Mechanistically, TBC1D15 was translocated to mitochondrial membranes in hepatocytes in response to alcohol exposure, where it recruited PLIN5 through its 10–180 aa domain. This interaction promoted mitochondria-LD contacts and facilitated PKA-induced nuclear translocation of PLIN5. Furthermore, TBC1D15 upregulated protein levels of PPARα, PGC1α and CPT1α in hepatocytes following alcohol challenge, an effect that was nullified by PKA inhibition.</div></div><div><h3>Conclusion</h3><div>TBC1D15 plays a promising protective role in ALD injury by enhancing mitochondrial function and FAO, potentially through its interaction with PLIN5 and modulation of mitochondria-LD contacts via PKA-mediated nuclear translocation of PLIN5. These findings identify TBC1D15 as a potential therapeutic target for ALD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156290"},"PeriodicalIF":10.8,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004157","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":"Dysregulation of CRY1 impairs brain thyroid hormone pathway and promotes anxiety-like behavior in male mice","authors":"Baojiang Lv ,&nbsp;Yuanyuan Liu ,&nbsp;Yu Yang ,&nbsp;Yedi Wu ,&nbsp;Zhengxin Chen ,&nbsp;Tianpeng Zhang ,&nbsp;Fangjun Yu ,&nbsp;Yafei Shi","doi":"10.1016/j.metabol.2025.156292","DOIUrl":"10.1016/j.metabol.2025.156292","url":null,"abstract":"<div><h3>Background</h3><div>The circadian clock system plays a crucial role in influencing mood and behavior, with the clock gene <em>Cry1</em> serving as a core component of the molecular circadian clock. However, the role of CRY1 in anxiety-related behaviors and their underlying mechanisms are poorly understood.</div></div><div><h3>Methods and results</h3><div>In this study, we investigated the role of CRY1 in anxiety-related behaviors through various behavioral approaches, and assessed potential molecular alterations in key brain regions involved in behavioral responses. We found that male <em>Cry1</em>^<em>-/-</em> (<em>Cry1</em> knockout) mice developed anxiety-like behavior in both stressed and non-stressed conditions. Administration of CRY1 stabilizer KL201 significantly alleviated anxiety-like behavior in male mice. Further studies suggested involvement of the brain thyroid hormone signaling in CRY1 regulation of anxiety-like behavior, evidenced by markedly reduced brain T3 levels relation to down-regulation of OATP1C1 and DIO2 mediated by CRY1, which underlies neurogenesis deficits and contributes to anxiety. Subsequent <em>in vivo</em> and cell-based experiments confirmed that CRY1 positively regulates the expression of OATP1C1 and DIO2. Mechanistically, CRY1 regulates OATP1C1 and DIO2 through regulating the transcriptional activity of E4BP4. E4BP4 trans-inactivates OATP1C1 and DIO2 via direct binding to its specific response element in the gene promoters.</div></div><div><h3>Conclusion</h3><div>These findings underscore the critical role of CRY1 in regulating thyroid hormone and anxiety, providing insight into the underlying pathogenesis and potential treatment strategies for mood disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156292"},"PeriodicalIF":10.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143934914","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":"Lactylation as a metabolic epigenetic modification: Mechanistic insights and regulatory pathways from cells to organs and diseases","authors":"Cong Chen ,&nbsp;Jie Wang ,&nbsp;Xueying Zhu ,&nbsp;Shan Zhang ,&nbsp;Xiandun Yuan ,&nbsp;Jun Hu ,&nbsp;Chao Liu ,&nbsp;Lanchun Liu ,&nbsp;Zhenpeng Zhang ,&nbsp;Jun Li","doi":"10.1016/j.metabol.2025.156289","DOIUrl":"10.1016/j.metabol.2025.156289","url":null,"abstract":"<div><div>In recent years, lactylation, a novel post-translational modification, has demonstrated a unique role in bridging cellular metabolism and epigenetic regulation. This modification exerts a dual-edged effect in both cancer and non-cancer diseases by dynamically integrating the supply of metabolic substrates and the activity of modifying enzymes: on one hand, it promotes tissue homeostasis and repair through the activation of repair genes; on the other, it exacerbates pathological progression by driving malignant phenotypes. In the field of oncology, lactylation regulates key processes such as metabolic reprogramming, immune evasion, and therapeutic resistance, thereby shaping the heterogeneity of the tumor microenvironment. In non-cancerous diseases, including neurodegeneration and cardiovascular disorders, its aberrant activation can lead to mitochondrial dysfunction, fibrosis, and chronic inflammation. Existing studies have revealed a dynamic regulatory network formed by the cooperation of modifying and demodifying enzymes, and have identified mechanisms such as subcellular localization and RNA metabolism intervention that influence disease progression. Nevertheless, several challenges remain in the field. This article comprehensively summarizes the disease-specific regulatory mechanisms of lactylation, with the aim of providing a theoretical foundation for its targeted therapeutic application.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156289"},"PeriodicalIF":10.8,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948633","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}