Metabolism: clinical and experimental最新文献

{"title":"Finerenone in the SGLT2i era: Redundancy or complementarity?","authors":"Hongyi Chen , Yuying Ma , Qiang Wang","doi":"10.1016/j.metabol.2025.156337","DOIUrl":"10.1016/j.metabol.2025.156337","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156337"},"PeriodicalIF":11.9,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528910","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":"Carboxylic acid metabolism in cancer: Mechanisms, microenvironment interactions, and therapeutic opportunities","authors":"Xiqing Bian ,&nbsp;Yue Zhuo ,&nbsp;Luo Zhou ,&nbsp;Yi Zhun Zhu ,&nbsp;Na Li ,&nbsp;Jian-Lin Wu","doi":"10.1016/j.metabol.2025.156334","DOIUrl":"10.1016/j.metabol.2025.156334","url":null,"abstract":"<div><div>Cancer cells reprogram their metabolism to favor aerobic glycolysis and enhance carboxylic acid metabolism, supporting their energy needs and promoting tumor progression. This review explores the role of carboxylic acids, such as lactate, fatty acids, and amino acids, in cancer through four key pathways: (1) lactate-mediated tumor microenvironment acidification and immune suppression, (2) fatty acid metabolism driving tumorigenesis, (3) amino acid regulation of cancer cell survival, and (4) the crosstalk between these metabolic networks. These pathways contribute to immune evasion, proliferation, and drug resistance by modulating key enzymes, transporters, and signaling mechanisms. Despite their therapeutic potential, targeting carboxylic acid metabolism remains challenging owing to tumor adaptability and metabolic heterogeneity. Future research directions include the development of isoform-specific inhibitors, combination therapies, and precision medicine approaches based on metabolic profiling. Understanding these interconnected pathways may reveal new vulnerabilities for innovative cancer treatments.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156334"},"PeriodicalIF":10.8,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518646","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":"Exosomal miRNAs in muscle-bone crosstalk: Mechanistic links, exercise modulation and implications for sarcopenia, osteoporosis and osteosarcopenia","authors":"Bo Zhang,&nbsp;Yang Chen,&nbsp;Qiaojie Chen,&nbsp;Haijun Zhang","doi":"10.1016/j.metabol.2025.156333","DOIUrl":"10.1016/j.metabol.2025.156333","url":null,"abstract":"<div><div>This review investigates the emerging role of exosomal microRNAs (miRNAs) as pivotal mediators of bidirectional communication between the skeletal muscle and bone tissue, with significant implications for age-related musculoskeletal disorders. In aging populations, sarcopenia often coexists with osteoporosis, forming osteosarcopenia, which markedly increases fracture risk, disability, and mortality. While traditional paradigms emphasize mechanical loading and endocrine pathways, emerging evidence has revealed that exosomes carrying bioactive miRNAs represent a novel class of paracrine factors in the muscle-bone axis. We examined how muscle-derived exosomal miRNAs (miR-34a and miR-27a-3p) influence bone metabolism, while bone-derived exosomal miRNAs (miR-486-5p) modulate muscle physiology. For each miRNA, we identified the target messenger RNAs (mRNAs) and signaling mechanisms. Importantly, exercise has emerged as a potent modulator of this crosstalk, altering exosomal miRNA profiles to promote anabolic outcomes in both tissues. This bidirectional communication contributes to osteosarcopenia pathophysiology, leading us to propose a novel “Exosomal miRNA Regulatory Network” for diagnosis and pathogenesis. Exosomal miRNAs show promise as early biomarkers for subclinical deterioration and therapeutic targets. However, methodological challenges in exosome isolation, incomplete characterization of miRNA networks, and aging complexity must be addressed before clinical implementation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156333"},"PeriodicalIF":10.8,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366945","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 bone-heart axis: A crucial dialogue in cardiovascular disease","authors":"Ying Liu ,&nbsp;Qi Yao ,&nbsp;Jiabin Yu,&nbsp;Yadan Zhang,&nbsp;Yang Xiao,&nbsp;Nan Zhang,&nbsp;Qi-Zhu Tang","doi":"10.1016/j.metabol.2025.156332","DOIUrl":"10.1016/j.metabol.2025.156332","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs), the leading cause of global mortality, are now understood to be profoundly influenced by the endocrine regulatory functions of the skeletal system. Emerging evidence suggests that osteocrine factors, including fibroblast growth factor-23 (FGF23), lipocalin-2 (LCN2), Dickkopf-1 (DKK1), myeloid-derived growth factor (MYDGF), osteocalcin (OCN), and sclerostin (SOST), establish bidirectional regulatory networks with the cardiovascular system, termed the “bone-heart axis”. This axis regulates critical pathological processes, including mineral metabolism, vascular calcification, and myocardial energy homeostasis. Dysregulation of this crosstalk accelerates the progression of atherosclerosis (AS), heart failure (HF), and other CVDs. Therefore, current research necessitates a paradigm shift from univariate analyses to elucidating the spatiotemporal dynamics of interorgan communication, thereby facilitating the development of precision therapeutic strategies for integrated skeletal and cardiovascular protection.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156332"},"PeriodicalIF":10.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340260","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":"Glycine as a conditionally essential amino acid and its relationship to l-serine","authors":"Milan Holeček","doi":"10.1016/j.metabol.2025.156330","DOIUrl":"10.1016/j.metabol.2025.156330","url":null,"abstract":"<div><div>Glycine is a conditionally essential amino acid obtained from food and synthesized in the body, primarily from <span>l</span>-serine. Glycine deficiency has been reported due to inadequate protein intake, malnutrition, late gestation, diabetes, insulin resistance, and increased exposure to xenobiotics. Because of the close links in glycine and <span>l</span>-serine metabolism mediated by serine hydroxymethyltransferase (SHMT), decreased concentrations of both amino acids coincide in most glycine-deficient states. The consequence is a widespread impact on metabolism, including altered synthesis of glutathione, collagen, nucleotides, and one‑carbon units, impaired antioxidant defense, cytoprotection, conjugation, and neurotransmission and increased levels of homocysteine and deoxysphingolipids. It can, therefore, be assumed that, rather than glycine alone, its coadministration with <span>l</span>-serine is more appropriate in glycine-deficient conditions. Replacing a part of the glycine with <span>l</span>-serine should avoid (i) glycine flux through SHMT towards <span>l</span>-serine associated with the loss of methylenetetrahydrofolate, a substance essential for methylation reactions, and (ii) ammonia formation due to glycine flux through the glycine cleavage system. Unfortunately, studies comparing the effects of separate administration of glycine and its coadministration with <span>l</span>-serine do not exist. Well-controlled studies in subjects without glycine deficit are required to examine the potential benefits of high doses of glycine as a pharmaconutrient.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156330"},"PeriodicalIF":10.8,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144307388","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":"Expanding the clinical and immunogenomic relevance of SAMD1 in hepatocellular carcinoma","authors":"Valbert Oliveira Costa Filho ,&nbsp;Pedro Robson Costa Passos","doi":"10.1016/j.metabol.2025.156331","DOIUrl":"10.1016/j.metabol.2025.156331","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"171 ","pages":"Article 156331"},"PeriodicalIF":11.9,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310205","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":"NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy","authors":"Jian Lv ,&nbsp;Junmei Wang ,&nbsp;Qin Chen ,&nbsp;Qianhua Zhong ,&nbsp;Hongchao Zhan ,&nbsp;Qiuxiao Guo ,&nbsp;Jiajie Li ,&nbsp;Ningning Guo ,&nbsp;Yu Fang ,&nbsp;Jingjing Tong ,&nbsp;Zhihua Wang","doi":"10.1016/j.metabol.2025.156324","DOIUrl":"10.1016/j.metabol.2025.156324","url":null,"abstract":"<div><div>Mitochondrial dysfunction is a hallmark of aging and has been implicated in aging-related diseases. NIPSNAP1 and NIPSNAP2 are functionally redundant homologs involved in mitochondrial quality control, yet their roles in healthy aging and longevity remain unclear. Here, we generated a <em>Nipsnap1/2</em> double knockout (DKO) mouse line and examined its impacts on mitochondrial physiology and natural aging. We demonstrated that the loss of <em>Nipsnap1/2</em> impaired mitochondrial function and enhanced glycolysis activity, but it did not affect mitophagy despite the significant accumulation of Parkin. Compared with wild-type mice, DKO mice exhibited reduced body weight, deteriorated muscle strength, and pronounced fragility at 24 months of age. Moreover, <em>Nipsnap1/2</em> depletion exacerbates aging-associated fibrosis and inflammation in the heart, liver and kidney. RNA-seq revealed a pro-aging transcriptome reprogramming toward energy exhaustion in DKO mice, eventually leading to cachexia-like adverse metabolic remodeling. Our findings demonstrate an anti-aging role of NIPSNAP1/2 via the surveillance of mitochondrial health.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156324"},"PeriodicalIF":10.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302488","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":"USP48 protects against myocardial ischemia-reperfusion injury by stabilizing and upregulating CNN1 in type 1 diabetes mice","authors":"Jia-Bao Su ,&nbsp;Guo Chen ,&nbsp;Qing-Yi Sun ,&nbsp;Xiao Fu ,&nbsp;Li-Xue Wu ,&nbsp;Hong-Bo Qiu ,&nbsp;Zhuo-Lin Lv ,&nbsp;Jin-Yi Hu ,&nbsp;Yao Wang ,&nbsp;You-Yi Zhuang ,&nbsp;Hai-Jian Sun ,&nbsp;Qing-Bo Lu ,&nbsp;Ji-Ru Zhang ,&nbsp;Xue-Xue Zhu","doi":"10.1016/j.metabol.2025.156326","DOIUrl":"10.1016/j.metabol.2025.156326","url":null,"abstract":"<div><div>Ubiquitin-specific protease 48 (USP48) plays an important role in the regulation of DNA repair and immune signaling in health and diseases. Nonetheless, its implication in the development of diabetes-accelerated myocardial ischemia/reperfusion (I/R) injury (MI/RI) has yet to be clarified. Diabetic mice were constructed by streptozotocin (STZ) injection, and MI/RI was then induced by coronary artery occlusion and reperfusion. H9c2 cells were exposed to high glucose (HG) for 24 h, followed by hypoxia/reoxygenation (H/R) for 4 and 2 h, respectively. USP48 protein and mRNA levels were downregulated in MI/RI mice or H/R-exposed cardiomyocytes, but were unexpectedly upregulated in diabetic mice following MI/RI and H9c2 cells exposed to HG and H/R. Cardiac-specific deficiency of USP48 worsened cardiac dysfunction, increased post-ischemic infarction size, promoted mitochondrial damage in myocardial cells, accelerated cardiomyocyte inflammation, oxidative stress, and apoptosis in diabetic mice. Conversely, such pathological conditions were ameliorated by cardiac-specific overexpression of USP48. Proteomics and experimental validation showed that USP48 stabilized and upregulated calponin 1 (CNN1) to confer cardioprotection, since silencing CNN1 minimized the benefits of USP48 in diabetes-aggravated cardiomyocyte injury. RNA sequencing and experimental data demonstrated that the USP48/CNN1 axis inhibited the release of CXC motif chemokine ligand 1 (CXCL1) and CXCL2 through inactivating the ERK1/2 pathway. Eventually, blockade of CXCL1/2 with specific antibodies protected against diabetes-exacerbated MI/RI, akin to USP48 overexpression. Together, these results highlight USP48 as a potential therapeutic target for managing diabetes-aggravated MI/RI by regulating the CNN1/ERK1/2/CXCL1/2 signaling pathway.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156326"},"PeriodicalIF":10.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144272223","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":"Exercise mitigates liver senescence but does not outmatch dietary restriction in obesity-related MASLD","authors":"Angeliki Katsarou ,&nbsp;Grigorios Papadopoulos ,&nbsp;Ioannis I. Moustakas ,&nbsp;Argyro Papadopetraki ,&nbsp;Athanasios Moustogiannis ,&nbsp;Aigli-Ioanna Legaki ,&nbsp;Eirini Giannousi ,&nbsp;George Agrogiannis ,&nbsp;Pavlos Pantelis ,&nbsp;Dimitris Veroutis ,&nbsp;Konstantinos Evangelou ,&nbsp;Athanassios Kotsinas ,&nbsp;Vassilis G. Gorgoulis ,&nbsp;Anastassios Philippou ,&nbsp;Michael Koutsilieris ,&nbsp;Antonios Chatzigeorgiou","doi":"10.1016/j.metabol.2025.156325","DOIUrl":"10.1016/j.metabol.2025.156325","url":null,"abstract":"<div><h3>Background</h3><div>The present study aims at deciphering the individual or combined benefits of aerobic exercise and dietary restriction on liver senescence, a state characterized by cell cycle arrest and simultaneous resistance to apoptosis, which is considered an established hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD).</div></div><div><h3>Methods</h3><div>C57BL6 mice were subjected to a normal diet (ND) for 20 weeks or a high-fat diet (HFD) supplemented with 5 % High-fructose Corn Syrup (HFCS) for 12 weeks, followed by eight-week interventions, including dietary restriction (DR), aerobic exercise (EX), a combination of both (DREX) or continuation of a HFD-HFCS diet without intervention. Biomarkers of senescence were analyzed in terms of their liver mRNA expression levels, while GL13 and p21^WAF1/CIP1 immunohistochemical stainings were conducted to examine the levels of senescence-associated lipofuscin and p21^WAF1/CIP1 respectively, to finally investigate their relationship with the grade of hepatic steatosis and fibrosis observed in the studied mice.</div></div><div><h3>Results</h3><div>DR and DREX groups exhibited significantly reduced features of obesity and MASLD-related hepatic steatosis and fibrosis, to a greater extent than the respective amelioration driven by aerobic exercise only in HFDEX animals. A statistically significant increase of mRNA expression was detected for cyclin-dependent kinase p21^WAF1/CIP1 in HFD livers as compared to ND, which was also reversed upon DR-inclusive interventions. Immunohistochemical stainings for GL13 and p21^WAF1/CIP1, as well as for p16^INK4A confirmed the aforementioned alterations of p21^WAF1/CIP1 at the tissular level while also revealed a p16^INK4A elevation in HFD livers which was reversed only upon DR/DREX.</div></div><div><h3>Conclusion</h3><div>Liver senescence is responsive both to exercise and dietary restriction, but its amelioration in the context of MASLD is more robust upon DR-inclusive interventions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156325"},"PeriodicalIF":10.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144272136","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":"Synergistic effects of C–C chemokine receptor 2 inhibitor and transforming growth factor-β type I receptor kinase inhibitor combination in metabolic dysfunction-associated steatohepatitis","authors":"Su Ho Jo ,&nbsp;Eun Soo Lee ,&nbsp;So Bin Lee ,&nbsp;Kyung Bong Ha ,&nbsp;Choon Hee Chung","doi":"10.1016/j.metabol.2025.156323","DOIUrl":"10.1016/j.metabol.2025.156323","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive hepatic disorder characterized by its association with metabolic abnormalities, including obesity, hyperlipidemia, and type 2 diabetes mellitus. Characterized by hepatic steatosis, inflammation, and fibrosis, MASH presents a significant global health challenge, with limited pharmacological options available. There is a critical need for novel therapeutic strategies targeting key molecular pathways involved in MASH pathogenesis. Combination therapy with these two drugs is expected to provide complementary preventive and therapeutic effects against MASH.</div></div><div><h3>Methods</h3><div>This study examined the therapeutic efficacy of a C–C chemokine receptor 2 (CCR2) inhibitor (RS-102895) in combination with a TGF-β type I receptor kinase inhibitor (vactosertib) in preclinical MASH models. Histological analysis, serum biomarker quantification, and gene expression profiling were performed to assess hepatic lipid accumulation, inflammation, fibrosis, and metabolic regulatory pathways.</div></div><div><h3>Results</h3><div>Combination therapy significantly improved histological parameters and reduced liver inflammation and fibrosis markers compared with monotherapy. Notably, it led to reductions in lipid accumulation and inflammatory cytokines, alongside the restoration of AMP-activated protein kinase (AMPK) activation, a key regulator of metabolic regulator. The study also identified the Rho-associated protein kinase 1 (ROCK1)/AMPK axis as a central mediator of MASH progression.</div></div><div><h3>Conclusions</h3><div>These findings indicate that dual inhibition of CCR2 and TGF-β signaling pathways could serve as an effective therapeutic approach for MASH. By addressing lipid accumulation, inflammation, and fibrosis while promoting metabolic balance, this strategy holds promise for improved clinical applications in treating this complex disease.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156323"},"PeriodicalIF":10.8,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266724","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}