Journal of molecular medicine (Berlin, Germany)最新文献

{"title":"Beyond the target: implications of Wnt pathway inhibitors on bone health.","authors":"Clement Nachef, Arnaud Vanjak, Eric Haÿ, Martine Cohen-Solal, Thomas Funck-Brentano","doi":"10.1007/s00109-026-02697-3","DOIUrl":"10.1007/s00109-026-02697-3","url":null,"abstract":"<p><p>Wnt signaling inhibitors are under investigation as potential therapies for conditions characterized by upregulated Wnt signaling, such as cancers, hematological disorders, and organ fibrosis. However, because the Wnt pathway is essential for bone homeostasis, its inhibition can adversely affect skeletal health. This review focuses on the bone-related off-target effects of Wnt inhibitors currently in clinical development, specifically those evaluated in Phase I and II trials with available published data. We found that inhibitors targeting upstream components of the pathway-such as Wnt ligands or receptors (e.g., porcupine inhibitors, Ipafricept, or Vantictumab)-frequently lead to bone-related adverse effects, including fractures and early trial termination. Co-administration of bisphosphonates may help mitigate these effects. In contrast, downstream inhibitors (e.g., PRI-724, niclosamide) have not been linked to bone toxicity, although this may reflect either underreporting or a genuinely lower skeletal impact. Further preclinical studies are warranted to better understand these differential effects. A thorough understanding of bone-specific risks is critical as Wnt signaling inhibitors continue to advance in clinical development.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13331953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148383490","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":"Non-transferrin-bound iron uptake by cardiomyocytes.","authors":"Qian Guo, Yao-Zhao Li, Zhong-Ming Qian, Christopher Qian","doi":"10.1007/s00109-026-02700-x","DOIUrl":"10.1007/s00109-026-02700-x","url":null,"abstract":"<p><p>Under conditions of iron overload, increased non-transferrin-bound iron (NTBI) can gain access to cardiomyocytes, cause cardiac iron accumulation and generate reactive oxygen species which can result in iron-overload cardiomyopathy. Currently, it is not fully understood how cardiomyocytes take up NTBI under iron-overload conditions. However, the large number of studies conducted over the past few decades have greatly improved our understanding of this critical issue in the field of heart disease, but so far there has been no effort to synthesize these studies and isolated ideas into a systematic and coherent summary. Herein, we focus on up-to-date advances in studies on the routes for cardiomyocytes to uptake NTBI, including L-type Ca2 + channels (LTCC), T-type Ca2 + channels (TTCC), divalent metal transporter 1 (DMT1), the Lipocalin-2 (LCN-2) / Lipocalin-2 receptor (LCN-2R) system and ZIP14 (SLC39A14). We also offer suggestions for addressing some critical gaps still extant in our understanding of this important topic.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148388526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative genetic and functional analysis of autosomal dominant hearing loss in 108 multigenerational families.","authors":"Dominika Oziębło, Marcin L Leja, Nina Gan, Natalia Bałdyga, Mohammad Reza Toliat, Birgit S Budde, Henryk Skarżyński, Monika Ołdak","doi":"10.1007/s00109-026-02692-8","DOIUrl":"10.1007/s00109-026-02692-8","url":null,"abstract":"<p><p>Autosomal dominant hearing loss (ADHL) is a highly heterogeneous Mendelian disorder with numerous causative genes, yet large well-characterized European cohorts remain limited. We investigated 108 families of Polish origin with confirmed dominant inheritance using a tiered strategy integrating targeted sequencing of 237 hearing loss genes, genome-wide linkage analysis, genome sequencing, segregation studies in 437 individuals, and functional validation by minigene splicing assays. This approach established a molecular diagnosis in 52% of families, with 67% of identified pathogenic variants being previously unreported. The genetic architecture proved highly heterogeneous, with recurrent contributions from MYO6, TBC1D24, WFS1, GSDME, and POU4F3 alongside numerous single-family findings. While missense variants predominated, splice-altering and truncating changes were also frequent. Importantly, genome-based analyses uncovered pathogenic mechanisms beyond canonical coding regions, including the first deep intronic EYA4 variant associated with ADHL and a large 3'UTR deletion in ATP11A affecting alternative transcripts. Functional assays confirmed aberrant splicing induced by synonymous, non-canonical splice-site, and deep intronic variants. These findings refine the gene-specific contribution to dominant hearing loss, expand the noncoding mutational landscape, and underscore the importance of integrating genomic and functional analyses for accurate variant interpretation and improved molecular diagnostics of hereditary hearing loss in clinical practice.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13314912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148348763","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":"Preclinical evaluation of cysteine protease-inhibitor aloxistatin (E64d) for heart failure therapy.","authors":"Maria Jordan, Angelika Stucki-Koch, Maximilian Schinke, Lena Willmer, Ingrid Senne, Naisam Abbas, Marco Bentele, Dana Oldenkott, Nico Lachmann, Linda Feldbrügge, Resa Puffert, Josef Fangmann, Robert Ramm, Thomas Thum, Katherina Sewald, Kevin Schmidt, Jan Fiedler","doi":"10.1007/s00109-026-02695-5","DOIUrl":"10.1007/s00109-026-02695-5","url":null,"abstract":"<p><p>Heart failure (HF) affects over 64 million people worldwide causally linked to fibrotic scarring. None of the available cardiac drugs target fibrosis directly, underlining unmet clinical need for novel therapies. This study aimed to explore the therapeutic potential of the cysteine protease inhibitor aloxistatin as a repurposed drug candidate to combat fibrotic progression in predictive HF models. Aloxistatin reduced migratory and proliferative capacities of human cardiac fibroblasts (HCFs) derived from various HF backgrounds. Mechanistically, aloxistatin attenuated TGFβ1-induced pro-fibrotic signaling in cardiomyopathy-derived HCFs by inhibiting extracellular matrix organization-related gene expression and secretion of MMP2 und FN1, partially mediated through CAPN2 inhibition. Transcriptomic analysis of rat ex vivo myocardial slices revealed a pronounced suppression of inflammatory pathways. Anti-inflammatory effects of aloxistatin were further confirmed by reduced NFκB activity in reporter cells and inhibited HLA-DR expression in human iPSC-derived macrophages. Application of diverse preclinical cardiac HF models arguably underlined aloxistatin as a potential drug repurposing strategy by simultaneously counteracting myocardial inflammatory signaling and pro-fibrotic mechanisms. This preclinical study suggests aloxistatin therapy for translational use to attenuate cardiac remodeling and progression of heart failure.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13294223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321596","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":"Zinc-binding protein metallothionein 3 protects vascular smooth muscle cells from ferroptosis via blocking lysosomal degradation of GPX4.","authors":"Wenxin Lin, Xin Feng, Jingjie Chen, Bo Huo, Xian Guo, Molin Yang, Ding-Sheng Jiang, Linling Yu, Yue Chen","doi":"10.1007/s00109-026-02696-4","DOIUrl":"10.1007/s00109-026-02696-4","url":null,"abstract":"<p><p>Aortic dissection (AD) is a life-threatening vascular emergency characterized by medial degeneration and vascular smooth muscle cell (VSMC) loss. Although disruption of zinc homeostasis has been reported in patients with AD, how zinc ions and their regulatory proteins influence VSMC survival and disease progression remains unknown. In this study, single-cell analyses revealed that ferroptosis and zinc-related pathways were significantly enriched in VSMCs from patients with AD, showing a strong correlation between the two processes, and zinc levels were markedly elevated in dissected aortas. Furthermore, zinc exposure promoted ferroptosis in cultured primary human aortic smooth muscle cells (HASMCs). By integrating transcriptomic data from AD tissues and VSMC ferroptosis models, metallothionein-3 (MT3), a zinc-binding protein, was identified as a candidate regulator. Functional studies demonstrated that MT3 overexpression markedly attenuated lipid peroxidation, reduced reactive oxygen species accumulation, and protected VSMCs from ferroptotic cell death, whereas MT3 knockdown increased oxidative stress and exacerbated ferroptotic injury. Mechanistically, MT3 directly interacted with glutathione peroxidase 4 (GPX4), enhanced its protein stability, without altering its transcriptional expression, and promoted glutathione synthesis, thereby activating the glutathione-GPX4 antioxidant defense pathway and mitigating oxidative injury. Notably, restoration of GPX4 effectively rescued the pro-ferroptotic effects of MT3 deficiency on HASMCs. These findings establish a previously unrecognized zinc-MT3-GPX4 axis as a critical determinant of VSMC ferroptosis in AD, linking zinc dysregulation to medial degeneration, and highlighting MT3 as a potential mechanistic candidate target to preserve vascular integrity and limit disease progression. KEY MESSAGES: Impaired zinc homeostasis is implicated in the development of aortic dissection (AD). Zinc-binding protein metallothionein 3 (MT3) mitigates lipid peroxidation and protects vascular smooth muscle cells from ferroptosis. MT3 directly interacts with glutathione peroxidase 4 (GPX4) to prevent its lysosomal degradation, thereby enhancing the glutathione-GPX4 antioxidant defense pathway. MT3 is a potential mechanistic candidate target for preserving vascular integrity and limiting AD progression.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148304577","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":"Clinical utility of cerebrospinal fluid interleukin-10 in central nervous system lymphoma: a molecular neuropathology-informed diagnostic meta-analysis.","authors":"Farnoosh Aalami, Alireza Mobasheri, Ali Shahriari, Amir H Aalami","doi":"10.1007/s00109-026-02688-4","DOIUrl":"10.1007/s00109-026-02688-4","url":null,"abstract":"<p><p>Accurate diagnosis of central nervous system lymphoma (CNSL) remains challenging, and cerebrospinal fluid (CSF) interleukin-10 (IL-10) has emerged as a promising minimally invasive biomarker. We conducted a PRISMA-DTA systematic review and diagnostic meta-analysis to evaluate the diagnostic performance of CSF IL-10 for CNSL and to examine its clinical utility and robustness using a reproducible Python-based workflow. Eleven studies comprising 1,462 participants (510 CNSL cases and 952 controls) met the inclusion criteria. Using a bivariate random-effects model, the pooled sensitivity and specificity were 79.8% (95% CI, 76.1-83.2) and 94.8% (95% CI, 93.2-96.0), respectively. The pooled positive likelihood ratio was 18.04 (95% CI, 8.35-38.98), the negative likelihood ratio was 0.185 (95% CI, 0.118-0.291), and the diagnostic odds ratio was 130.55 (95% CI, 47.85-356.14). The summary receiver operating characteristic curve demonstrated excellent overall accuracy, with an area under the curve of 0.973 and a Q* index of 0.9246. Leave-one-out sensitivity analysis showed only modest changes in the pooled estimates, supporting the stability of the results. Δ-sensitivity ranged from - 1.9% to + 3.0% and Δ-specificity from - 1.1% to + 2.0%, supporting robustness. Fagan's analysis, using a pre-test probability of 34.9%, yielded post-test probabilities of 90.6% following a positive result and 9.0% following a negative result. Publication bias was suggested by Begg's test (τ = 0.400, p = 0.0434) and Egger's test (intercept = 3.283, 95% CI, 1.337-5.229; p = 0.0021), while trim-and-fill analysis indicated potential small-study effects. Overall, CSF IL-10 demonstrates high diagnostic accuracy and strong rule-in utility for CNSL. However, prospective multicenter studies with standardized thresholds and pre-analytical protocols are needed to confirm its clinical applicability.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148285067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular regulation of PGC-1α: from protein-protein interactions and post-translational modifications to pharmacological modulation.","authors":"William Q Rios, Carlos M Silva, Rita Ferreira, José R B Gomes","doi":"10.1007/s00109-026-02694-6","DOIUrl":"10.1007/s00109-026-02694-6","url":null,"abstract":"<p><p>Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a master transcriptional coactivator responsible for regulating cellular energy metabolism and mitochondrial biogenesis across high-energy tissues such as the heart, skeletal muscle, and brown adipose tissue. To orchestrate its regulatory functions, PGC-1α interacts with a diverse array of transcription factors such as peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs), which is facilitated by its dynamic three-dimensional structure, the presence of distinct functional domains, and the ability to be modulated via post-translational modifications. This review examines the protein's interactions with key nuclear receptors and the biological consequences of these complexes, including the regulation of thermogenesis, gluconeogenesis, and fatty acid oxidation. Furthermore, we discuss the extensive post-translational modifications-including phosphorylation, acetylation, methylation, O-GlcNAcylation, and ubiquitination-that tightly regulate PGC-1α stability and coactivation efficiency. Finally, this review highlights recent progress in the identification of small molecule modulators, such as the activator ZLN005 and the inhibitor SR18292, evaluating their physiological outcomes and potential as therapeutic agents for metabolic disorders and cancer, while addressing the challenges posed by the protein's structural disorder in drug discovery.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148280739","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":"Molecular determinants of thromboinflammatory activation in inflammatory bowel disease.","authors":"Roko Šantić, Nikola Pavlović, Marko Kumrić, Marino Vilović, Joško Božić","doi":"10.1007/s00109-026-02693-7","DOIUrl":"10.1007/s00109-026-02693-7","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is consistently associated with an increased risk of venous thromboembolism, particularly during active disease and hospitalization, yet thrombosis in this context extends beyond a transient inflammatory complication. Emerging evidence supports a unifying thromboinflammatory framework in which chronic intestinal inflammation promotes systemic vascular activation. Endothelial dysfunction represents a central interface in this process and is characterized by reduced nitric oxide bioavailability, increased expression of adhesion molecules, angiogenic remodeling, and glycocalyx disruption, collectively shifting the vascular surface toward a proadhesive and procoagulant phenotype. In parallel, dysregulation of coagulation pathways sustains thrombin generation through enhanced tissue factor signaling, elevated procoagulant factors, most consistently factor VIII, impaired endogenous anticoagulant mechanisms including the protein C and antithrombin systems, and features of hypofibrinolysis. Platelet activation further amplifies these disturbances via CD40 ligand (CD40L)-mediated endothelial crosstalk, platelet leukocyte aggregate formation, and imbalance of the von Willebrand factor (VWF)-ADAMTS13 axis, reinforcing a self perpetuating loop between inflammation and coagulation. Although mechanistic plausibility is strong and multiple biomarkers of endothelial and hemostatic activation have been described, much of the current evidence derives from cross sectional or associative studies, with limited prospective validation linking individual pathways to incident thrombotic outcomes in IBD specific cohorts. Taken together, thrombosis in IBD reflects sustained systemic thromboinflammatory dysregulation rather than an isolated complication of flares. Future longitudinal studies integrating vascular biomarkers with adjudicated thrombotic events are essential to refine risk stratification and inform individualized thromboprophylaxis strategies.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148261201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oleanolic acid modulates neuronal regeneration through KLF5-mediated FGF13 mRNA degradation to alleviate Alzheimer's disease-like cognitive dysfunction.","authors":"Dan Ren, Jiangxi Xu, Lan Xiao, Ting Zhang, Biyan Li, Ruomeng Li, Hong Zhu","doi":"10.1007/s00109-026-02691-9","DOIUrl":"10.1007/s00109-026-02691-9","url":null,"abstract":"<p><p>Despite understanding the pathophysiology of Alzheimer's disease (AD), the mechanisms of neuronal regeneration mediated by oleanolic acid (OA) through m6A RNA methylation remain unexplored, forming the crux of this study. In a streptozotocin (STZ)-induced AD rat model, we administered OA and conducted behavioral tests to evaluate cognitive functions. We employed BrdU incorporation assays and immunofluorescence to investigate NSC proliferation, and Western blotting, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and MeRIP-qPCR assays to analyze protein expression and RNA stability. Bioinformatic predictions focused on the interaction between KLF5, YTHDF2, and FGF13. OA significantly reversed cognitive impairment and enhanced NSC differentiation in the AD model. The modulation of OA on KLF5 expression led to the repression of YTHDF2, which was pivotal in the m6A-dependent RNA decay of FGF13, promoting axonal regeneration. Furthermore, FGF13 harbors multiple m6A modification sites, which contribute to its mRNA stability and translation, thereby influencing neuronal polarization and migration. In addition, the neuroprotective mechanism of OA also involved the upregulation of NSCs, while impaired neurogenesis and reduced NSC function are known to be associated with AD pathology. This research reveals that OA's therapeutic potential in AD is mediated through a previously unidentified mechanism involving modulation of m6A-dependent RNA regulation, highlighting the significance of m6A RNA methylation in neuronal regeneration. The findings pave the way for new therapeutic strategies targeting RNA modifications in neurodegenerative diseases.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148255474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lentiviral GLP-1 gene therapy elicits developmental stage-dependent β-cell regeneration in diabetic rats.","authors":"Ezgi Erbasan, Melike Aliciaslan, Fulya Erendor, Sumeyye Sensoy, Busra Cetin, Mustafa Aydemir, Salih Sanlioglu","doi":"10.1007/s00109-026-02690-w","DOIUrl":"10.1007/s00109-026-02690-w","url":null,"abstract":"<p><p>Pancreatic β-cell differentiation and regenerative capacity differ markedly between developmental stages, with the neonatal pancreas exhibiting high plasticity that enables ongoing progenitor- and ductal-derived β-cell formation, whereas the adult pancreas demonstrates limited neogenic potential. Glucagon-like peptide-1 (GLP-1) promotes β-cell survival, proliferation, and differentiation; however, its developmental stage-specific effects on β-cell regeneration are not fully understood. To investigate this, we generated a third-generation HIV-based lentiviral vector encoding native GLP-1 (LentiGLP-1) under the control of cytomegalovirus (CMV) promoter using the Multisite Gateway^® recombination cloning system. The vector's ability to modulate β-cell differentiation and proliferation was subsequently assessed in neonatal and adult diabetic rat models. Type 2 Diabetes (T2DM) was induced in neonatal rats by administering low-dose streptozotocin (STZ), exploiting the intrinsic plasticity of the developing pancreas, whereas in adult rats, a high-fat diet combined with low-dose STZ was used. LentiGLP-1 administration markedly promoted differentiation of ductal and progenitor cells into insulin-producing β-cells in neonatal rats, accompanied by enhanced β-cell proliferation, demonstrating effective engagement of developmental plasticity. In adults, LentiGLP-1 partially restored β-cell populations through activation of residual progenitors and stimulation of replication in existing β-cells, improving glycemic control and insulin sensitivity. Notably, acinar cells did not contribute to β-cell generation in either neonatal or adult models. These results indicate that GLP-1 exerts developmentally regulated effects on β-cell differentiation, facilitating neogenesis in neonates and partially restoring regenerative capacity in adults. Long term GLP-1 expression, thus represents a promising strategy to restore β-cell mass by proliferation and differentiation, providing insight into its therapeutic potential for diabetes.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13260127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148230529","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}