Molecular biomedicine最新文献

{"title":"H2A.J is an epigenetic driver of IL-17-associated inflammation in T_H17 cells and keratinocytes.","authors":"Tanja Kübelbeck, Anna Stastny, Niklas Beumer, Antonia Kolb, Tanja Knopp, Berenice Fischer, Dennis Fritsche, Ana-Marija Kulis-Mandic, Matthias Klein, Mariia Antipova, Bettina Mros, Michael Delacher, Ari Waisman, Carl Mann, Claudia E Rübe, Susanne Karbach, Björn E Clausen, Carsten Deppermann, Miriam Wittmann, Daniela Kramer","doi":"10.1186/s43556-026-00611-4","DOIUrl":"10.1186/s43556-026-00611-4","url":null,"abstract":"<p><p>Psoriasis is a common autoinflammatory disease driven by excessive IL-17 expression. While the pathomechanism of the disease has been revealed, epigenetic factors contributing to psoriasis are less well understood. Here, we investigated the role of the poorly studied histone variant H2A.J in psoriasis. We found that H2A.J gets overexpressed in the skin of psoriasis patients, with even non-lesional skin showing increased expression compared to the skin of healthy donors. To gain mechanistic insights, we studied mice with a global H2A.J knockout (KO) and found them to be partially protected against experimentally induced psoriasis, highlighted by reduced immune cell infiltration and less hyperkeratosis. Molecularly, psoriatic skin of H2A.J KO mice showed diminished expression of chemokines and cytokines, including CXCL1, CCL3, and IL-17A. This phenotype could partially be explained by the role of H2A.J as a key regulator of IL-17A-responsive genes in keratinocytes. Furthermore, we uncovered a T-cell-intrinsic function of H2A.J, which specifically promoted the expression of effector molecules such as Il17a and Il17f in T_H17 cells. Our findings from human skin and murine psoriasis models imply that H2A.J acts as a key epigenetic regulator of IL-17-associated inflammation, which controls the (chronic) activation of T_H17 cells and keratinocytes in psoriasis.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149139684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate-induced MBD2 K186 lactylation promotes YAP1-dependent myofibroblast-like remodeling of Müller cells in diabetic retinopathy.","authors":"Xindan Xing, Yan Jiang, Junwei Fang, Xin Shi, Qian Zhu, Yinchen Shen, Li Su, Xinyi Liu, Hanying Wang, Jin Wei, Yuan Qu, Kangjia Lv, Yu Xiao, Jingtong Xie, Xiaoxin Liu, Hancong Wan, Tian Niu, Kun Liu","doi":"10.1186/s43556-026-00605-2","DOIUrl":"10.1186/s43556-026-00605-2","url":null,"abstract":"<p><p>Tractional retinal detachment caused by fibroproliferative membrane formation is a vision-threatening complication of proliferative diabetic retinopathy (PDR). Müller cells can acquire myofibroblast-like features during retinal fibroproliferative remodeling, yet the metabolic mechanisms governing these phenotypic changes remain poorly understood. Here, we report that lactate is a metabolic regulator of myofibroblast-like remodeling in Müller cells. Metabolomic profiling revealed elevated vitreous lactate levels in patients with PDR. Consistently, lactate concentrations were increased in the vitreous and retinal tissues of diabetic rats, whereas high-glucose exposure promoted lactate accumulation in primary Müller cells. Increased lactate availability enhanced Müller cell proliferative activity and migration, as well as the expression of myofibroblast-associated proteins, including α-smooth muscle actin, smooth muscle protein 22, and collagen I, whereas oxamate, an inhibitor of lactate dehydrogenase, attenuated these responses. Lactylome profiling and molecular validation revealed K186 of methyl-CpG-binding domain protein 2 (MBD2) as a functionally relevant lactylation site. RNA sequencing of high-glucose-treated Müller cells expressing MBD2-K186R versus MBD2-WT revealed reduced YAP1 expression in the K186R group, suggesting that YAP1 is a downstream effector of MBD2 K186 lactylation. Mechanistically, increased lactate availability enhanced MBD2 K186 lactylation and YAP1 activation, as evidenced by reduced inhibitory phosphorylation of YAP1 and increased nuclear accumulation of YAP1. MBD2 K186R attenuated YAP1 activation and myofibroblast-like changes, whereas YAP1 overexpression partially reversed these effects. Collectively, these findings reveal a lactate-MBD2 K186 lactylation-YAP1 signaling axis that promotes myofibroblast-like remodeling of Müller cells and may contribute to fibroproliferative pathology in PDR.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bariatric surgery may alleviate MASLD by restoring mitochondria-lipid droplet structural and functional integrity through suppression of the Mitochondrial Fission Factor-Perilipin 5 axis.","authors":"Yuze Sun, Yuxuan Liu, Xiyu Chen, Shizhou Deng, Ning Zhang, Feifei Wu, Dong Fan, Yayun Wang, Yanling Yang","doi":"10.1186/s43556-026-00607-0","DOIUrl":"10.1186/s43556-026-00607-0","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent chronic liver diseases worldwide, characterized primarily by excessive lipid droplet (LD) accumulation in hepatocytes. Bariatric surgery, particularly sleeve gastrectomy (SG), represents the most effective intervention for reversing MASLD, although the underlying mechanisms remain incompletely understood. This study aimed to investigate the mitochondrial and lipid droplets (LDs) related molecular mechanisms by which SG ameliorated MASLD. Using a high-fat diet (HFD)-induced mouse model of MASLD, combined with SG intervention, hepatocyte-specific genetic manipulation, multi-omics analysis, and mitochondrial ultrastructural examination, we observed that MASLD was associated with a marked upregulation of perilipin 5 (PLIN5) on the LD surface and mitochondrial fission factor (MFF) on the mitochondrial outer membrane. Ultrastructural and co-immunoprecipitation (Co-IP) analyses revealed that PLIN5 and MFF formed a complex that facilitated the recruitment of LDs to mitochondria and their penetration into the mitochondrial matrix. This process ultimately led to disrupted mitochondrial fatty acid β-oxidation and structural disorganization. SG significantly downregulated PLIN5 and MFF expression, reduced LD-induced mitochondrial damage, and enhanced mitochondrial resilience to high-fat stress. These changes might contribute to the restoration of mitochondria-LD structural and functional homeostasis, ultimately reversing MASLD. Our findings indicated that aberrant upregulation of MFF contributed to MASLD progression, and SG might alleviate the disease by suppressing the MFF-PLIN5 axis to normalize mitochondria-LD interactions. These results suggested that targeting the MFF-PLIN5 axis may offer a promising therapeutic strategy for non-surgical management of MASLD.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of SPP1 + macrophages and their correlation with resistance to neoadjuvant chemotherapy in colorectal cancer liver metastasis.","authors":"Jingzhi Tang, Weijie Hao, Xigan He, Xin Qian, Linjie Ruan, Mengyao Quan, Jian Zhou, Jing Tang, Lu Wang, Yi Guo, Yiming Zhao, Cai Chang, Shichong Zhou","doi":"10.1186/s43556-026-00581-7","DOIUrl":"https://doi.org/10.1186/s43556-026-00581-7","url":null,"abstract":"<p><p>Neoadjuvant chemotherapy (NAC) for colorectal cancer liver metastasis (CRLM) remains a major clinical challenge, with outcomes varying widely among patients, yet the mechanisms that drive therapeutic resistance remain incompletely understood. In this study, we integrated single‑cell RNA‑sequencing and spatial transcriptomics of patient tumor specimens to dissect the interplay between the hepatic tumor microenvironment and chemotherapy resistance. We identified a specific macrophage subpopulation marked by elevated expression of Secreted Phosphoprotein 1 (SPP1) that is significantly enriched in insufficient responders to NAC. Mechanistically, these SPP1 + macrophages exhibit a pro‑tumoral transcriptomic profile and directly suppress CD8 + T cell cytotoxic function through the SPP1‑CD44 signaling axis, as demonstrated by in vitro co‑culture assays, a large‑scale tissue microarray, and multiple syngeneic mouse models. Spatially, they are scattered throughout the tumour and form dense barriers that sequester CD8 + T cells and drive their exhaustion. Strikingly, this spatial configuration inversely correlates with cytotoxic activity and adaptive immune signatures and thereby reinforces a local immunosuppressive niche that sustains chemoresistance. These data provide the missing link: effective chemotherapy requires an immune‑active hepatic microenvironment, and SPP1 + macrophage infiltration actively disrupts this state, which in turn promotes clinical resistance. In a preclinical CRLM model, SPP1 blockade synergised with anti‑PD‑1, inducing significant tumour regression and restoring T‑cell function. Collectively, our findings position SPP1 + macrophages as central drivers of NAC resistance in CRLM and highlight the spatial immune barrier they create as a promising therapeutic target for overcoming chemoresistance and improving immunotherapy responses.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncolytic virus encoding decorin and the CD40 ligand boosts T-cell response and achieves a durable antitumor response during breast cancer treatment.","authors":"Yingjun Ning, Yejing Rong, Haifeng Meng, Yudong Lin, Wanqian Chen, Qiaoyun Shi, Sijia Zhang, Hongshan Li, Yuefeng Yang","doi":"10.1186/s43556-026-00570-w","DOIUrl":"https://doi.org/10.1186/s43556-026-00570-w","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) remains an aggressive disease with limited treatment options. Oncolytic adenoviruses represent a promising platform, but their efficacy as single agents is often insufficient. This study examined whether an oncolytic adenovirus co-delivering decorin (DCN) and CD40 ligand (CD40L), designated rAd.DCN.CD40L, could enhance antitumor activity and immune activation against TNBC. Recombinant adenoviruses expressing DCN (rAd.DCN), CD40L (rAd.CD40L), or both proteins were constructed and evaluated in breast cancer cells using cell viability, apoptosis, migration, invasion, and damage-associated molecular pattern (DAMP) release assays. Compared with rAd.DCN or rAd.CD40L alone, rAd.DCN.CD40L triggered greater apoptosis and tumor cell death and elicited more pronounced DAMP release. Co-culture experiments also revealed enhanced dendritic cell function following rAd.DCN.CD40L treatment. For in vivo evaluation, syngeneic 4T1 and EMT-6 subcutaneous tumor models and a 4T1 lung metastasis model were employed. rAd.DCN.CD40L substantially delayed tumor growth and improved survival in tumor-bearing mice. Flow cytometric and histological analyses further confirmed enhanced local and systemic T-cell responses, elevated CD8⁺ T-cell activity, and modulated inflammatory macrophage phenotypes. Mechanistically, western blot analysis showed that rAd.DCN.CD40L may contribute to extracellular matrix remodeling and the down-regulation of the expression of epithelial-mesenchymal transition (EMT)-associated genes. Notably, CD8⁺ T-cell depletion markedly attenuated the therapeutic efficacy of rAd.DCN.CD40L, demonstrating that CD8⁺ T cells are critical functional effectors of tumor control. Collectively, these findings indicate that a DCN- and CD40L-armed oncolytic adenovirus represents a promising combinatorial strategy for TNBC immunotherapy, and warrants further preclinical and clinical investigation.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the CD4⁺ effector memory T cells re-expressing CD45RA suppressor galectin-7: a multi-omics-guided therapeutic strategy for idiopathic pulmonary fibrosis.","authors":"Tao Yan, Jichang Liu, Yong Liu, Wenchao Gu, Jia Liu, Yuanshu Li, Rongrong Lv, Chuanpeng Zhang, Jiaqi Ding, Chenlong Zha, Chaoqun Wang, Fei Gao, Man Huang, Jingyu Chen","doi":"10.1186/s43556-026-00542-0","DOIUrl":"https://doi.org/10.1186/s43556-026-00542-0","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with limited therapeutic options. Although single-cell and spatial transcriptomics have revealed cellular heterogeneity within the IPF lung microenvironment, the immune drivers with causal relevance remain poorly defined. Here, through large-scale Mendelian randomization integrating multi-omics data, we identified a consistent negative causal association between the proportion of CD4⁺ effector memory T cells re-expressing CD45RA (TEMRA) and IPF risk. Multi-platform validation-including single-cell RNA sequencing, flow cytometry, and multiplex immunofluorescence-confirmed a significant reduction in CD4⁺ TEMRA frequency in both peripheral blood and lung tissues of IPF patients, establishing this subset as a clinically relevant biomarker. Spatial transcriptomics further revealed a negative correlation between TEMRA differentiation signatures and local fibrotic burden. Mechanistically, integrated single-cell analyses pinpointed metaplastic KRT5⁺ basal cells as a key epithelial population with the capacity to disrupt immune homeostasis. These aberrant epithelial cells upregulate Galectin-7 (LGALS7), which we demonstrate competes with IL-7 for receptor binding, suppresses STAT5 phosphorylation, and limits CD4⁺ TEMRA differentiation, thereby uncovering a previously unrecognized epithelial-immune crosstalk axis in IPF. Guided by these findings, virtual screening of 20,000 compounds identified neoeriocitrin as a Galectin-7 inhibitor that restores STAT5 phosphorylation in vitro and attenuates pulmonary fibrosis in vivo. This study positions Galectin-7 as a druggable target and establishes a novel framework linking epithelial dysfunction to immune dysregulation in IPF.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile acid signaling in health and disease.","authors":"Zhezhe Fan, Mengyi He, Taiping Liang, Bili Zhang, Na Zhao, Pan Li","doi":"10.1186/s43556-026-00603-4","DOIUrl":"https://doi.org/10.1186/s43556-026-00603-4","url":null,"abstract":"<p><p>Bile acids (BAs), cholesterol-derived amphipathic metabolites which are traditionally regarded as digestive surfactants, are now recognized as pleiotropic signaling molecules that act through ligand-, receptor-, and tissue-specific mechanisms to maintain systemic homeostasis. They exert biological functions via nuclear receptors (FXR, PXR, VDR, CAR) and membrane receptors (TGR5, S1PR2, MRGPRX4). These receptors activate transcriptional and membrane-initiated programs, including FXR-SHP/FGF19 feedback, TGR5-cAMP-PKA signaling, S1PR2-ERK/AKT/RhoA pathways, MRGPRX4-dependent Ca²⁺ signaling, PXR/CAR/VDR-driven detoxification responses, and non-receptor-mediated membrane and mitochondrial stress pathways. This review discusses how the diversity of BA structures, hepatic synthesis, conjugation, transportation, enterohepatic circulation, and microbiota-mediated transformation generates receptor- and tissue-specific signals. Furthermore, we summarize the physiological functions of BA signaling in lipid, glucose, and energy metabolism, intestinal epithelial integrity, mucosal immunity, neuroendocrine regulation, musculoskeletal adaptation, and renal water-salt balance. Additionally, we discuss the effects of disrupted BA signaling on cholestatic and metabolic liver diseases, alcohol-associated liver disease, hepatocellular carcinoma, inflammatory bowel disease, BA diarrhea, colorectal cancer, obesity, type 2 diabetes, atherosclerosis, and biliary tract diseases. Finally, the therapeutic strategies that modulate BA signaling, including the use of FXR and TGR5 agonists, FGF19 analogues, transporter inhibitors, enzyme-targeting methods, microbiota-based treatments, and hydrophilic BA therapies, are evaluated. By categorizing BA biology according to the production of ligands, receptor activation, tissue responses, and disease mechanisms, this review highlights BA signaling as an integrated regulatory network and a tractable therapeutic axis in health and disease.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spermine: an endogenous iron chelator that suppresses ferroptosis.","authors":"Yutian Xia","doi":"10.1186/s43556-026-00614-1","DOIUrl":"https://doi.org/10.1186/s43556-026-00614-1","url":null,"abstract":"","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision base-editing of the cryptic 3' acceptor site to correct the RNA splicing defect of β⁶⁵⁴-thalassemia.","authors":"Dan Lu, Xiuli Gong, Xinbing Guo, Qin Cai, Wenxiu Li, Yanwen Chen, Dali Li, Fanyi Zeng","doi":"10.1186/s43556-026-00589-z","DOIUrl":"https://doi.org/10.1186/s43556-026-00589-z","url":null,"abstract":"<p><p>β-Thalassemia is one of the most common inherited disorders worldwide and is caused by mutations affecting β-globin production. β⁶⁵⁴ mutation (IVS2-654, C > T) is one of the most frequently occurring β-thalassemia alleles in Han Chinese population, which activates a cryptic 3' splice site and leads to aberrant RNA splicing. Previous studies demonstrated that direct base editing of the IVS2-654 mutation is challenging because suitable single-guide RNAs (sgRNAs) cannot effectively target this site. Here we investigated an alternative therapeutic strategy by targeting the mutation-activated cryptic 3' splice acceptor site, rather than the disease-causing mutation itself. We first introduced base substitutions into the cryptic splice acceptor site in a β⁶⁵⁴-thalassemia mouse model using CRISPR-Cas9-mediated homology-directed repair, which restored normal RNA splicing and validated the therapeutic rationale of this approach. We then generated base-edited β⁶⁵⁴ mice by microinjecting Td-CBEmax mRNA together with sgRNAs targeting the cryptic splice acceptor site into one-cell embryos. Base editing was successfully achieved in 78% of live-born β⁶⁵⁴ mice, of which 86% produced correctly spliced β-globin transcripts. Restoration of normal RNA splicing was accompanied by marked improvement of hematological parameters and tissue pathology in most base-edited founder mice and their offspring compared with non-edited β⁶⁵⁴ mice. Together, these findings demonstrate that mutation-activated cryptic splice sites are therapeutically actionable targets for precision base editing and provide proof of concept for a precise and effective strategy to correct aberrant RNA splicing in β⁶⁵⁴-thalassemia.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SGLT2 inhibitors: mechanisms, physiology and pharmacology, and clinical applications.","authors":"Xue-Ting Zheng, Hui-Yi Xie, Xiu-Heng Wang, Yue Zhao, Jia-Yan Yang, Yun-Xi Liu, Xian-Liang Yuan, Hui-Fang Tang, Zhi-Sheng Jiang, Heng-Jing Hu","doi":"10.1186/s43556-026-00604-3","DOIUrl":"https://doi.org/10.1186/s43556-026-00604-3","url":null,"abstract":"<p><p>Sodium-glucose cotransporter 2 (SGLT2) is a low-affinity, high-capacity transporter expressed predominantly in the renal proximal tubule, where it mediates the sodium-coupled reabsorption of most filtered glucose. SGLT2 inhibitors have evolved from glucose-lowering agents into disease-modifying therapies across the cardio-renal-metabolic continuum. Blockade of proximal tubular transport induces glycosuria, osmotic diuresis, restoration of tubuloglomerular feedback, resetting of renal haemodynamics, and altered fluid compartmentalisation. These early renal and circulatory effects interact with systemic metabolic adaptations, including pseudo-starvation signalling, erythropoiesis, altered uric acid handling, and changes in substrate availability. At the cellular level, SGLT2 inhibition has been linked to improved ionic homeostasis and mitochondrial quality control, reduced oxidative stress, modulation of inflammation, and attenuation of maladaptive tissue remodelling. Endothelial injury may connect these cellular effects with microvascular dysfunction and fibrosis. Endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT) offer a mechanistic framework for understanding the relationship between microvascular injury and fibrosis. However, EndMT is best viewed as one component of a broader endothelial-stromal stress response rather than as a single proven mediator of clinical benefit. These pharmacodynamic and cellular effects help explain the consistent clinical efficacy of SGLT2 inhibitors across type 2 diabetes, chronic kidney disease, and heart failure (HF), while also informing emerging applications in acute HF, after myocardial infarction, and in patients with arrhythmia or metabolic dysfunction-associated steatohepatitis. This Review integrates mechanistic, pharmacological, and clinical evidence to identify unresolved translational gaps and future directions, including mechanism-informed biomarkers, imaging, spatial multi-omics, phenotype-guided patient stratification, dual sodium-glucose cotransporter 1/2 inhibition, and rational combination therapy.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149119814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}