JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

{"title":"Molecular Mechanisms of CLCN5 Missense Mutations in Dent Disease Type 1: A Comprehensive Computational Analysis and Clinical Correlations in a Chinese Cohort","authors":"Chengpeng Wu,&nbsp;Ying Zhang,&nbsp;Zipei Chen,&nbsp;Haidong Fu,&nbsp;Zhi Du,&nbsp;Liqun Chen,&nbsp;Guozhen Wang,&nbsp;Jianhua Mao,&nbsp;Lidan Hu","doi":"10.1111/jcmm.71108","DOIUrl":"10.1111/jcmm.71108","url":null,"abstract":"<p>Dent's disease, an X-linked recessive disorder predominantly affecting males, is characterized by nephrocalcinosis, nephrolithiasis, and a high risk of progression to end-stage renal disease. Dent's disease type 1, accounting for 60% of cases, caused by mutations in the <i>CLCN5</i> gene encoding the chloride ion channel protein ClC-5, exhibits significant clinical heterogeneity and variability in disease progression. The lack of hotspot mutations poses challenges for genetic diagnosis and counselling, complicating the prediction of disease outcomes. This study systematically evaluated the functional and structural impacts of 181 <i>CLCN5</i> missense mutations using computational tools, including PredictSNP, MAGPIE, and molecular dynamics simulations, to propose a robust method for improving genetic counselling and prognosis prediction. Our analysis identified mutations at the dimer interface and chloride selectivity filter as critical disruptors of ClC-5 function and stability. Notably, molecular dynamics simulations of L200R, P213L, and G512R mutations revealed that L200R significantly destabilized the protein structure. Clinical data from a multicentre cohort of Chinese patients with <i>CLCN5</i> mutations corroborated our computational predictions, highlighting the essential role of helix O in ClC-5 function. By integrating bioinformatics analyses with clinical validation, this study provides molecular insights into Dent's disease heterogeneity and proposes a framework for enhancing genetic counselling and prognostic assessment for affected patients.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.71108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147486112","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":"Consequences of CRISPR-Cas9-Mediated Stromelysin-1 Knockout in Pancreatic Islet Microvascular Endothelial Cells","authors":"Bing Wang,&nbsp;Weiqi Liu,&nbsp;Yuan Li,&nbsp;Qin Ouyang,&nbsp;Yingyu Wang,&nbsp;Xiang Xu,&nbsp;Bingwei Li,&nbsp;Ruijuan Xiu,&nbsp;Xu Zhang,&nbsp;Mingming Liu","doi":"10.1111/jcmm.71098","DOIUrl":"10.1111/jcmm.71098","url":null,"abstract":"<p>The integrity of the pancreatic islet microvasculature is critical for endocrine function, yet it is progressively compromised by glucotoxicity in diabetes. While matrix metalloproteinases are implicated, the role of stromelysin-1 as a potential upstream driver of endothelial dysfunction remains poorly defined. The aim of our study was to elucidate the role of stromelysin-1 in mediating glucotoxic injury to islet microvascular endothelial cells (IMECs). To this end, we employed a CRISPR/Cas9-mediated knockout of stromelysin-1 in IMECs. Cellular functions, including proliferation, migration, and angiogenesis, were assessed using IncuCyte ZOOM live-cell imaging, while endothelial barrier integrity was quantified via a 40 kDa dextran flux assay. Additionally, the secretome was profiled using a cytokine antibody array. We found that genetic ablation of stromelysin-1 conferred protection against glucotoxicity. Stromelysin-1 KO IMECs exhibited significantly enhanced proliferation, migration, and angiogenic capacity compared to wild-type controls. Furthermore, stromelysin-1 deficiency restored endothelial monolayer integrity by attenuating high-glucose-induced hyperpermeability. These functional improvements were linked to a remodelling of the secretome, characterised by decreased secretion of the pro-degradative MMP-2 and increased secretion of the anti-inflammatory cytokine IL-10 and the endogenous inhibitor TIMP-2. Overall, our findings establish stromelysin-1 as a crucial mediator of glucotoxic injury in islet microvascular endothelial cells.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.71098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147486167","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":"Apolipoprotein E Deficiency Impairs Human Microglial Proliferation Accompanied by Elevated Cellular Oxidative Stress","authors":"Dayoung Kim,&nbsp;Takayuki Kondo,&nbsp;Keiko Imamura,&nbsp;Kayoko Tsukita,&nbsp;Ayako Nagahashi,&nbsp;Tomoki Sakasai,&nbsp;Haruhisa Inoue","doi":"10.1111/jcmm.71074","DOIUrl":"10.1111/jcmm.71074","url":null,"abstract":"<p>The <i>APOE</i> gene, which encodes Apolipoprotein E (ApoE), is the strongest genetic risk locus for Alzheimer's disease (AD). A substantial fraction of AD risk genes converges on pathways controlling lipid metabolism and immune regulation, in which microglia serve as a central integrative hub in the brain. Although microglial phenotypes linked to different <i>APOE</i> genotypes have been extensively characterised, the fundamental question of how ApoE shapes the core functions of human microglia remains unresolved. Here, we generated <i>APOE</i> knockout (KO) microglia from AD patient–derived induced pluripotent stem cells (iPSCs) and characterised their cellular and molecular phenotypes. Ablation of <i>APOE</i> resulted in marked lipid droplet accumulation and increased NLRP3 inflammasome activation. Transcriptomic analysis further revealed downregulation of cell cycle–related pathways, accompanied by enrichment of an oxidative stress–associated pathway. Consistent with these transcriptomic signatures, <i>APOE</i> KO microglia exhibited elevated intracellular reactive oxygen species (ROS) levels and a marked reduction in proliferative capacity. Given the importance of microglial proliferation for maintaining immune homeostasis in the brain, our findings highlight ApoE as being an important regulator of this process, with potential consequences for the pathogenesis of neurodegenerative disorders.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.71074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147486101","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":"Honokiol and Magnolol Exert an Anti-Inflammatory Effect by Inhibiting JAK2/STAT3/IL17 Signalling in a Rat Model of Ulcerative Colitis: A Combination of Bioinformatics and Experimental Study","authors":"Zhaoxu Cai,&nbsp;Shaojun Lu,&nbsp;Jingan Chen,&nbsp;Xiaoshan Yang,&nbsp;Junlin Lu,&nbsp;Changwen Feng","doi":"10.1111/jcmm.71080","DOIUrl":"10.1111/jcmm.71080","url":null,"abstract":"<p>Ulcerative colitis (UC) is a chronic, inflammatory bowel disease with limited clinical treatment. Traditional Chinese medicinal ingredients honokiol and magnolol have potential anti-inflammatory and gastrointestinal protective effects. However, their anti-inflammatory potential has not been investigated in UC. This study hypothesized that honokiol and magnolol alleviate UC by targeting key inflammatory signalling pathways. To verify this, we established a 2,4-dinitrobenzenesulfonic acid-induced UC rat model and administered honokiol and magnolol orally. The results showed that the two ingredients significantly reduced the disease activity index and colonic mucosal damage index and downregulated serum levels of pro-inflammatory factors TNF-α, IL-17, and CRP. Histopathological examination showed marked alleviation of colonic mucosal hyperemia, inflammatory infiltration, and ulcerative damage following honokiol and magnolol treatment. Bioinformatics analysis identified 74 UC-related targets for honokiol and 62 for magnolol, which were enriched in inflammatory response and JAK–STAT/IL-17 signalling pathways. A gradient boosting machine model was established to screen 16 shared hub targets, among which IL17A, JAK2, and STAT3 were highly correlated with immune cell infiltration. Molecular docking confirmed that honokiol and magnolol could stably bind to key proteins of the JAK–STAT pathway via noncovalent interactions with low binding energy. Immunohistochemistry and Western blot further verified that both ingredients significantly inhibited the activation of IL17A, JAK2, and STAT3 in the colonic tissues of UC rats. This study demonstrates that honokiol and magnolol exert anti-inflammatory effects in UC rats by inhibiting the JAK2/STAT3/IL17 pathway, providing a mechanistic basis and potential targets for the application of traditional Chinese medicinal ingredients in UC treatment.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.71080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147480727","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":"Nicotinamide (Vitamin B3) Deficiency in Follicular Fluid of Patients With Ovarian Ageing","authors":"Cinzia Bocca,&nbsp;Magalie Boguenet,&nbsp;Lisa Boucret,&nbsp;Pierre-Emmanuel Bouet,&nbsp;Pascal Reynier,&nbsp;Pascale May-Panloup","doi":"10.1111/jcmm.71085","DOIUrl":"10.1111/jcmm.71085","url":null,"abstract":"<p>Nicotinamide is an essential precursor of NAD involved in energy metabolism. A decline in NAD levels across tissues during ageing is well-documented, and NAD metabolism has been implicated in ovarian ageing. We investigated the relationship between ovarian ageing and the levels of nicotinamide (NAM) and its metabolite 1-methylnicotinamide (MNA) in follicular fluid (FF) and blood of IVF patients. FF was obtained from 86 patients with ovarian ageing and 82 controls. Serum samples were collected from 24 and 29 patients, respectively. Nicotinamide and 1-methylnicotinamide levels were quantified by HPLC-MS/MS. Nicotinamide concentration was significantly decrease in the FF of patients with ovarian ageing (<i>p</i> &lt; 0.01), associated by an increase in 1-methylnicotinamide concentration (<i>p</i> = 0.01), leading to a sharp increase of the MNA/NAM ratio (<i>p</i> &lt; 0.001). This ratio negatively correlated with antral follicle count, anti-Mullerian hormone level and the number of oocytes retrieved, while positively correlating with age. Additionally, there was a positive correlation between the ratio values in FF and serum. Our results suggest an imbalance towards the nicotinamide degradation pathway in ovarian ageing, potentially impairing the NAD salvage pathway. They argue in favour of using nicotinamide to counteract ovarian ageing in patients and suggest the assessment of MNA/NAM ratio as a biomarker.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.71085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147480730","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":"Correction to ‘Integrating Bulk RNA and Single-Cell RNA Sequencing Identifies and Validates Lactylation-Related Signatures for Intervertebral Disc Degeneration’","authors":"","doi":"10.1111/jcmm.71061","DOIUrl":"10.1111/jcmm.71061","url":null,"abstract":"<p>Y. Shi, F. Li, W. Lin, L. Han, J. Wang, C. Yan, J. Sun, C. Ji, J. Shi, and K. Sun, “Integrating Bulk RNA and Single-Cell RNA Sequencing Identifies and Validates Lactylation-Related Signatures for Intervertebral Disc Degeneration,” <i>Journal of Cellular and Molecular Medicine</i> 28, no. 23 (2024): e70262. https://doi.org/10.1111/jcmm.70262</p><p>In the article, there was an error in Figure 10H. The hematoxylin-eosin (HE) and safranin O and fast green (SF) image of the Ctrl group in Figure 10H are incorrect. This error arose from an inadvertent typesetting oversight during the figure assembly process. Specifically, due to file naming similarities, an incorrect image was accidentally selected and placed in the ctrl panel instead of the correct representative image. These corrections do not alter the results or conclusions of the article.</p><p>The correct Figure 10H is shown below.</p><p>We sincerely apologise for this error.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.71061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147473850","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":"DMRTA2 Regulates Radial Glial Maintenance and Tumorigenicity of Paediatric High-Grade Glioma","authors":"Hitomi N. Royston,&nbsp;Autumn B. Hampton,&nbsp;Elissa G. Oliver,&nbsp;Jayden Jackson,&nbsp;Ibukunoluwa Tella,&nbsp;Miriam D. Emerson,&nbsp;Dhruv Bhagat,&nbsp;Grace E. Zimmerman,&nbsp;Daijiro Konno,&nbsp;Kosuke Funato","doi":"10.1111/jcmm.71092","DOIUrl":"10.1111/jcmm.71092","url":null,"abstract":"<p>DMRTA2 is a member of the evolutionarily conserved transcription factor family involved in various developmental processes including neurogenesis. However, the roles of DMRTA2 in human development and disease are not fully characterised. Single cell RNA-seq data analysis showed that DMRTA2 is robustly expressed in neural progenitors, in particular radial glial (RG) cells, in the human fetal brain. Knockout of the <i>DMRTA2</i> gene in human embryonic stem cell (hESC)-derived cerebral organoids led to smaller organoid size and fewer RG cells. We also found that DMRTA2 is highly and specifically expressed in diffuse hemispheric gliomas, H3G34-mutant (DHG-H3G34), a malignant subtype of paediatric brain tumour. Loss of DMRTA2 resulted in enhanced neuronal differentiation, fewer RG-like glioma cells and impaired tumorigenicity, suggesting its important role in both normal brain development and the formation of malignant brain tumours.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.71092","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147473761","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":"Increased CD44 Expression in Endothelial Cells Induced by Advanced Glycation End Products Leads to Insufficient Maturation of Angiogenesis","authors":"Xiaoxia Huang,&nbsp;Zhuanhua Liu,&nbsp;Jiaqing Hu,&nbsp;Bingyu Li,&nbsp;Zhenfeng Chen,&nbsp;Tairan Zeng,&nbsp;Xing Zhou,&nbsp;Ruimin Lu,&nbsp;Wenyan Deng,&nbsp;Wendong Zhou,&nbsp;Qiaobing Huang","doi":"10.1111/jcmm.71088","DOIUrl":"10.1111/jcmm.71088","url":null,"abstract":"<p>Pathological angiogenesis occurs in various diseases, including tumours, diabetes and wound healing. The endothelial cells lining these aberrant neovessels exhibit abnormal morphology, with loosely attached or absent pericytes and the basement membrane (BM) is often disrupted. Advanced glycation end products (AGEs) promote pathological angiogenesis in diabetic vascular complications, but whether the vascular BM structure is altered and the underlying molecular mechanisms remain unclear. By analysing single-cell RNA sequencing data (GSE204880) from the oxygen-induced retinopathy mouse model, this study found heterogeneous expression of type IV collagen (Col-IV) and laminin in endothelial cells, with enrichment of the AGE-RAGE pathway and BM-related pathways. Experimental results demonstrated that AGEs induce abnormal distribution of Col-IV in vascular BM, along with increased Col-IV levels in mouse serum and endothelial-pericyte co-culture supernatants, suggesting excessive BM degradation. Additionally, AGEs upregulated CD44 and matrix metalloproteinases 9 (MMP9) protein levels in retinal tissues and endothelial cells. Knockout/knockdown of CD44 or inhibition of MMP9, can both significantly alleviate BM structural disruption and abnormal angiogenesis. The down-regulation of CD44 expression or application of γ-secretase inhibitor DAPT attenuated AGEs-promoted MMP9 expression and secretion. Moreover, AGEs facilitated β-catenin nuclear translocation and its interaction with TCF4. When this interaction was blocked by LF3, AGEs-induced CD44 upregulation was reduced, and pathological angiogenesis and BM abnormalities were partially restored. These findings suggest that AGEs upregulate endothelial CD44 expression via β-catenin/TCF4 signalling pathway, which in turn promotes MMP9-mediated excessive degradation of BM components, leading to structural disorganisation and impaired vascular maturation in pathological angiogenesis.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.71088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147468013","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":"Nonlinear Bivariate Associations and Mononuclear Cell-Type-Specific Expression Level Differences in the STING Signalling Pathway","authors":"David Kaplan,&nbsp;Eric L. Christian","doi":"10.1111/jcmm.71093","DOIUrl":"10.1111/jcmm.71093","url":null,"abstract":"<p>Understanding intracellular signalling pathways is crucial since they regulate essential functional activities. Bivariate relationships have been useful in delineating these pathways in clinical samples. In our previous studies, we have found many linear associations between pathway components, and we have interpreted these correlations as rheostatic regulators. Increases in an upstream component are correlated with a commensurate downstream increase. Here, we report a quantitative analysis of molecules in the STING pathway by assessing the variance in human peripheral blood mononuclear cell-type-specific molecular expression from patients with atherosclerotic coronary artery disease. The induction of the type I interferon track by this pathway is dependent on the expression levels of STING in T cells and monocytes and the expression levels of phospho-STING in B cells. This relationship in T cells and monocytes demonstrates definitive linearity, indicating that it is regulated as a rheostat. In B cells the relationships are logarithmic, indicating an on-off mechanism of regulation. The STING pathway-dependent stimulation of the NFκB track is also controlled by on-off mechanisms that are modelled by nonlinear bivariate relationships. These on-off switches occur at the bifurcation of the two branches involving phospho-STING, phospho-TBK1 and phospho-RelA. Whereas linear bivariate associations are readily captured by an evaluation of the correlation matrix, significant nonlinear relationships are not. Nonlinear correlations modelled logarithmically or exponentially are easily discerned by the assessment of a natural log-transformed versus non-transformed correlation matrix.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.71093","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147468111","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":"The SGLT2 Inhibitor Canagliflozin Promotes β-Cell Regeneration and Restores and Stabilises β-Cell Identity in a Polygenic Model of Severe Early-Onset Type 2 Diabetes","authors":"Iuliana Popescu,&nbsp;Robert C. Bunn,&nbsp;Phil Ray,&nbsp;Kathryn M. Thrailkill,&nbsp;John L. Fowlkes","doi":"10.1111/jcmm.71041","DOIUrl":"10.1111/jcmm.71041","url":null,"abstract":"<p>Childhood obesity has led to an increase in type 2 diabetes (T2D) among youth, with adolescent-onset T2D showing a rapid decline in β-cell function compared to adult-onset cases. While the disease progression is more aggressive in early life, treatment can lead to recovery or remission more often at younger ages. SGLT2i have proven multiple health benefits when prescribed to adults with T2D but may have a greater potential in improving insulin production and β-cell mass in youth. In our study, TallyHO mice, which develop severe early-onset T2D, were treated with canagliflozin (cana) while on a 10-week diet. Results showed a significant reduction in blood glucose levels and improved β-cell function, indicated by higher C-peptide, islet insulin content, and HOMA-B index compared to untreated mice. Cana treatment restored the islet area and β to α-cell ratio, while also decreasing apoptosis. Notably, cana promoted the transient appearance of endocrine bihormonal cells and small clusters of insulin-positive cells, suggesting a possible transdifferentiation process and β-cell neogenesis. Furthermore, cana stabilised β-cell phenotype, restoring the expression of key identity markers while reducing abnormal cell types and the dedifferentiation to precursors and mesenchymal cells. These findings suggest that canagliflozin can promote the regeneration of pancreatic islets and mitigate β-cell dedifferentiation in the early onset of β-cell deficiency.</p>","PeriodicalId":101321,"journal":{"name":"JOURNAL OF CELLULAR AND MOLECULAR MEDICINE","volume":"30 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.71041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147433036","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}