{"title":"ATM deficiency drives phenotypic diversity and Purkinje cell degeneration in a macaque model of ataxia-telangiectasia.","authors":"Kaiyu Xu, Ying Zhang, Yongxuan Chen, Xiaojia Zhu, Yu Li, Longbao Lv, Xiechao He, Zhengfei Hu, Yifan Li, Maosen Ye, Dewei Jiang, Zhanlong He, Weihua Jin, Yanyan Li, Xiaomei Yu, Deng-Feng Zhang, Karl Herrup, Ping Zheng, Yong-Gang Yao, Dong-Dong Wu, Jiali Li","doi":"10.1016/j.xcrm.2025.102355","DOIUrl":"10.1016/j.xcrm.2025.102355","url":null,"abstract":"<p><p>Ataxia-telangiectasia (A-T) is a hereditary neurodegenerative disorder caused by mutations in the ATM (ataxia-telangiectasia mutated) gene. Although existing rodent models reproduce some of the multi-systemic features of A-T, they notably fail to recapitulate the severe neurological manifestations, particularly the profound cerebellar atrophy and associated ataxia. To address this limitation, we have generated ATM-deficient rhesus macaques using CRISPR-Cas9. These macaques exhibit hallmark features of A-T, including growth retardation, lymphopenia, elevated a-fetoprotein levels, oculocutaneous telangiectasias, heightened sensitivity to ionizing radiation, and most critically, cerebellar atrophy, Purkinje cell loss, and early-stage cerebellar neurodegeneration leading to significant motor impairments. Single-nucleus transcriptomic profiling of the cerebellum revealed pronounced gene expression changes associated with ATM deficiency, particularly in molecular layer interneurons (MLIs), which are implicated in Purkinje cell loss. This non-human primate model provides deeper insights into the pathogenesis of A-T and represents a promising and valuable platform for developing therapeutic strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 9","pages":"102355"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jia-Hui Christy Ang, Lijuan Sun, Sik-Yin Roger Foo, Melvin Khee-Shing Leow, Antonio Vidal-Puig, Luigi Fontana, Mayank Dalakoti
{"title":"Perspectives on whole body and tissue-specific metabolic flexibility and implications in cardiometabolic diseases.","authors":"Jia-Hui Christy Ang, Lijuan Sun, Sik-Yin Roger Foo, Melvin Khee-Shing Leow, Antonio Vidal-Puig, Luigi Fontana, Mayank Dalakoti","doi":"10.1016/j.xcrm.2025.102354","DOIUrl":"10.1016/j.xcrm.2025.102354","url":null,"abstract":"<p><p>Metabolic flexibility is the body's ability to switch between fuel sources in response to changing supply. This adaptability is crucial for maintaining energy balance and metabolic homeostasis, involving key processes like insulin signaling, organ-specific hormone regulation, and mitochondrial function. Initially thought to be determined by skeletal muscle, metabolic flexibility is now recognized as a systemic process affecting multiple organs, including the brain, liver, heart, and adipose tissue. In cardiometabolic diseases, metabolic inflexibility often occurs early, contributing to disease progression. Insulin resistance, a key factor in metabolic inflexibility, impairs fuel utilization and exacerbates metabolic syndrome. Understanding and addressing metabolic flexibility is critical for early detection and prevention. This review emphasizes the significance of metabolic flexibility in cardiometabolic health, underscoring the importance of endocrine regulation and organ crosstalk. However, knowledge gaps remain regarding the mechanisms linking metabolic inflexibility to disease, the need for better clinical assessments, and the relationship with insulin resistance.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 9","pages":"102354"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Inhibiting KRAS with CD47 and immune checkpoint overcomes intrinsic resistance to combined KRAS and immune checkpoint inhibitor therapy.","authors":"Kentaro Hirade, Noritaka Tanaka, Taisuke Kajino, Yuta Adachi, Ryo Kimura, Hitomi Kasuya, Satoru Kisoda, Tze King Tan, Sho Hayakawa, Takahiko Sato, Shogo Yanase, Yoko Kitaura, Takamasa Yamamoto, Yuki Nishioka, Osamu Muto, Daisuke Muraoka, Teruaki Fujishita, Natsumi Kasuga, Kageaki Watanabe, Yoshihiko Sakata, Masahiro Aoki, Hirokazu Matsushita, Takaomi Sanda, Shinsuke Iida, Kohsuke Tsuchiya, Rui Yamaguchi, Hiromichi Ebi","doi":"10.1016/j.xcrm.2025.102317","DOIUrl":"10.1016/j.xcrm.2025.102317","url":null,"abstract":"<p><p>Although Kirsten rat sarcoma virus (KRAS) G12C inhibitors alter the treatment strategy for patients with KRAS G12C-mutant lung cancer, their efficacy remains insufficient to eliminate tumors. Here, we identify that inhibition of mutant KRAS promotes escape from macrophage phagocytosis by upregulating the expression of cluster of differentiation 47 (CD47) and CD24. These proteins are induced by the binding of FOXA1 to the super-enhancer of CD47 and grainyhead-like transcription factor 2 (GRHL2) to the promoter of CD24, respectively. Whereas the addition of an anti-CD47 antibody restores macrophage phagocytosis, phagocytic macrophages induce programmed death-ligand 1 (PD-L1) expression, resulting in the suppression of CD8 T cell activation. Combination of a KRAS inhibitor with anti-CD47 and anti-PD-L1 antibodies achieves long-term survival in an orthotopic murine model recalcitrant to KRAS inhibition with immune checkpoint therapy. These results suggest that targeting KRAS with an anti-CD47 antibody and immune checkpoint blockade is a promising strategy, especially in immune-cold lung tumors.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102317"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cristina Gómez-Martín, Esther E E Drees, Monique A J van Eijndhoven, Nils J Groenewegen, Steven Wang, Sandra A W M Verkuijlen, Jan R T van Weering, Ernesto Aparicio-Puerta, Leontien Bosch, Kris A Frerichs, Christie P M Verkleij, Marie J Kersten, Josée M Zijlstra, Daphne de Jong, Catharina G M Groothuis-Oudshoorn, Michael Hackenberg, Johan R de Rooij, Niels W C J van de Donk, D Michiel Pegtel
{"title":"Circulating extracellular vesicle isomiR signatures predict therapy response in patients with multiple myeloma.","authors":"Cristina Gómez-Martín, Esther E E Drees, Monique A J van Eijndhoven, Nils J Groenewegen, Steven Wang, Sandra A W M Verkuijlen, Jan R T van Weering, Ernesto Aparicio-Puerta, Leontien Bosch, Kris A Frerichs, Christie P M Verkleij, Marie J Kersten, Josée M Zijlstra, Daphne de Jong, Catharina G M Groothuis-Oudshoorn, Michael Hackenberg, Johan R de Rooij, Niels W C J van de Donk, D Michiel Pegtel","doi":"10.1016/j.xcrm.2025.102358","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102358","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a plasma cell neoplasm characterized by high inter- and intra-patient clonal heterogeneity, leading to high variability in therapeutic responses. Minimally invasive biomarkers that predict response may help personalize treatment decisions. IsoSeek, a single-nucleotide resolution small RNA sequencing method can profile thousands of microRNAs (miRNAs) and their variants (isomiRs) from patient plasma-purified extracellular vesicles (EVs). Machine learning-generated miRNA/isomiR classifiers accurately predict therapeutic response in relapsed/refractory MM (RRMM) patients receiving daratumumab-containing regimens, achieving an area-under-the-curve of 0.98 (95% confidence interval [CI]:0.94-1.00). A classifier signature with the plasma cell-selective miR-148-3p, predicts durable response (≥6 months), progression-free (hazard ratio [HR]: 33.09, 95% CI: 4.2-262, p < 0.001), and overall survival (HR: 3.81, 95% CI: 1.05-13.99, p < 0.05). Targetome analysis connects the prognostic classifier to established MM drug targets BCL2 and MYC suggesting biological relevance. Thus, EV-isomiR sequencing in MM patients offers a tumor-naïve alternative to an invasive bone-marrow biopsy for predicting treatment outcome.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102358"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079704","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}
Cell Reports MedicinePub Date : 2025-09-16Epub Date: 2025-08-27DOI: 10.1016/j.xcrm.2025.102315
Kai Kang, Shanghai Liu, Zhuoran Yao, Jianxin Xue, You Lu
{"title":"Addressing clinical needs in NSCLC immunotherapy: Mechanisms of resistance and promising combination strategies.","authors":"Kai Kang, Shanghai Liu, Zhuoran Yao, Jianxin Xue, You Lu","doi":"10.1016/j.xcrm.2025.102315","DOIUrl":"10.1016/j.xcrm.2025.102315","url":null,"abstract":"<p><p>PD-(L)1 monoclonal antibody-based immunotherapy has become the cornerstone of treatment for non-small cell lung cancer without driver gene alterations. However, resistance, including primary and acquired resistance, remains a major clinical challenge. In this review, we summarize the delayed separation of progression-free survival curves observed in randomized clinical trials, which reflects the emergence of resistance at different treatment stages and the dynamic evolution of anti-tumor immune responses. The development of effective combination strategies should therefore be guided by a thorough understanding of the complex biological mechanisms governing tumor-immune interactions. We review the underlying mechanisms of immunotherapy resistance and propose potential combination strategies. Finally, we emphasize several key considerations for future clinical trial design, including the sequencing of combination therapies, biomarker-guided treatment selection, and optimized management of treatment-related toxicities.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102315"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-09-16Epub Date: 2025-08-25DOI: 10.1016/j.xcrm.2025.102305
Aisha M Swaih, Sara Talbot, Adriana Savoca, Hannah Thorpe, Vikki Flemington, Benjamin Phillips, Nicola Colclough, William McCoull, Veronika Radeva, David Hargreaves, Martin J Packer, Catarina Felisberto-Rodrigues, Clare Thomson, Jonathan P Orme, Carly Deane, Aaron Smith, Peter Johnström, Magnus Schou, Lisa McWilliams, Paul Davey, Marianne Enget, Daniel O'Neill, Sabina Cosulich, Nicolas Floc'h
{"title":"AZ14289671 is a highly selective and blood-brain barrier penetrant irreversible TKI that targets EGFRExon20 insertions.","authors":"Aisha M Swaih, Sara Talbot, Adriana Savoca, Hannah Thorpe, Vikki Flemington, Benjamin Phillips, Nicola Colclough, William McCoull, Veronika Radeva, David Hargreaves, Martin J Packer, Catarina Felisberto-Rodrigues, Clare Thomson, Jonathan P Orme, Carly Deane, Aaron Smith, Peter Johnström, Magnus Schou, Lisa McWilliams, Paul Davey, Marianne Enget, Daniel O'Neill, Sabina Cosulich, Nicolas Floc'h","doi":"10.1016/j.xcrm.2025.102305","DOIUrl":"10.1016/j.xcrm.2025.102305","url":null,"abstract":"<p><p>Current clinical therapeutics against non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (EGFRExon20Ins) mutations yield limited responses particularly against brain metastases; therefore, there is a need for an effective tyrosine kinase inhibitor (TKI). AZ14289671 is an oral, potent, irreversible, selective, and blood-brain barrier penetrant TKI targeting EGFRExon20Ins mutations while sparing wild-type (WT) EGFR. Preclinical assessments using cell lines, cell line-derived xenograft, and patient-derived xenograft models harboring EGFRExon20Ins demonstrate that AZ14289671 exhibits strong signaling pathway inhibition and highly sustained tumor regression against multiple EGFRExon20Ins, whereas its activity against WT is minimal. Additionally, AZ14289671 can cross the blood-brain barrier. This has the potential to improve outcomes of NSCLC patients with EGFRExon20Ins.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102305"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-09-16Epub Date: 2025-08-19DOI: 10.1016/j.xcrm.2025.102303
Karoliina Tuomela, Rosa V Garcia, Dominic A Boardman, Pedram Tavakoli, Maria Ancheta-Schmit, Ho Pan Sham, Lihong Cheng, Mary Struthers, Brian Bressler, Bruce A Vallance, Qihong Zhao, Megan K Levings
{"title":"TYK2 inhibition enhances Treg differentiation and function while preventing Th1 and Th17 differentiation.","authors":"Karoliina Tuomela, Rosa V Garcia, Dominic A Boardman, Pedram Tavakoli, Maria Ancheta-Schmit, Ho Pan Sham, Lihong Cheng, Mary Struthers, Brian Bressler, Bruce A Vallance, Qihong Zhao, Megan K Levings","doi":"10.1016/j.xcrm.2025.102303","DOIUrl":"10.1016/j.xcrm.2025.102303","url":null,"abstract":"<p><p>Janus kinase (JAK) inhibitors are widely used to inhibit inflammatory cytokine signaling in autoimmune and inflammatory diseases, but their effect on regulatory T cells (Tregs) is poorly characterized. We investigated the effect of a JAK inhibitor, upadacitinib, on human Treg differentiation and phenotype in comparison to BMS-986202, a selective Tyrosine kinase 2 (TYK2) inhibitor. Both upadacitinib and BMS-986202 blocked naive CD4<sup>+</sup> T cell differentiation into Th1/17 cells, but only BMS-986202 and a related TYK2 inhibitor, deucravacitinib, spared interleukin-2 (IL-2) signaling and Treg induction. BMS-986202 also increased Treg suppressive function and stability under Th1/17-polarizing conditions, whereas upadacitinib significantly impaired the phenotype and viability of ex vivo Tregs. In lamina propria mononuclear cells from patients with inflammatory bowel disease cultured under Th17-polarizing conditions, BMS-986202 redirected CD4<sup>+</sup> T cells toward a Treg phenotype. The Treg-sparing and enhancing properties of TYK2 inhibition suggest that TYK2 inhibitors are a promising pharmacological approach for tolerance induction.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102303"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chunlei Zheng, Asif Khan, Daniel Ritter, Debora S Marks, Nhan V Do, Nathanael R Fillmore, Chris Sander
{"title":"Pancreatic cancer risk prediction using deep sequential modeling of longitudinal diagnostic and medication records.","authors":"Chunlei Zheng, Asif Khan, Daniel Ritter, Debora S Marks, Nhan V Do, Nathanael R Fillmore, Chris Sander","doi":"10.1016/j.xcrm.2025.102359","DOIUrl":"10.1016/j.xcrm.2025.102359","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a rare, aggressive cancer often diagnosed late with low survival rates, due to the lack of population-wide screening programs and the high cost of early detection methods. To enable early detection of high-risk individuals, we develop a transformer-based model trained on longitudinal Veterans Affairs electronic health record (EHR) with 19,426 PDAC cases and ∼15.9 million controls. Our model combines diagnostic and medication trajectories to predict PDAC risk within a 6-, 12-, and 36-month assessment window. Incorporating medication significantly improved performance; among the top 1,000-5,000 highest-risk patients in a cohort of 1 million patients, 3-year PDAC incidence is 115-70 times higher than a reference estimate based on age and sex alone. Furthermore, analysis of most predictive features highlights the role of events such as chronic inflammatory conditions and specific medications on overall PDAC risk. Our work provides an AI-driven identification of high-risk individuals, with a potential to improve early detection, enhance patient care, and reduce healthcare costs.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 9","pages":"102359"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Oral virome metagenomic catalog links Porphyromonas gingivalis phages to obesity and type 2 diabetes.","authors":"Tiansong Xu, Xianyue Jiao, George Liu, Xi Chen, Qingqing Luo, Gaopu Zhang, Bowen Li, Yu Zhang, Xue Li, Yoo Cheung, Xiaofen Chai, Yueqing Huang, Huihui Wu, Feng Deng, Feng Chen, Guanxiang Liang","doi":"10.1016/j.xcrm.2025.102325","DOIUrl":"10.1016/j.xcrm.2025.102325","url":null,"abstract":"<p><p>The human microbiota has a critical role in maintaining human microbiome homeostasis and health, yet the viral component of the oral microbiome remains largely unidentified. We establish the Human Oral Virome Database (HOVD) catalog, a freely accessible online resource cataloging 24,440 bacteriophage viral operational taxonomic units and 83 eukaryotic viral genomes. Utilizing HOVD, we investigate oral virome variation and its correlation with oral bacteria and gut virome in 220 obese individuals with or without type 2 diabetes mellitus (T2D). Obese individuals with T2D exhibit reduced oral viral diversity, lower correlations with clinical features, disrupted viral-bacterial correlations, and enhanced oral-gut virome transmission. Furthermore, we computationally identify bacteriophages that infect Porphyromonas gingivalis and screen six putative endolysins. Experimental validation reveals that a mixture of three endolysins significantly inhibits Porphyromonas gingivalis growth. These findings highlight the potential of phage-derived endolysins for periodontitis with T2D, offering a path toward oral and systemic disease intervention.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102325"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effect of henagliflozin on aging biomarkers in patients with type 2 diabetes: A multicenter, randomized, double-blind, placebo-controlled study.","authors":"Jie Zhang, Wei Cai, Danfeng Liu, Nianfeng Zheng, Youping Wang, Fenglin Qiu, Huoping Zheng, Huaxia Gan, Yuqing Huang, Yan Zhou, Meiling Yu, Shuping Xiong, Guigen Luo, Jianping Guo, Lingyan Zhu, Yan Zhang, Huanying Ke, Yu Liu, Guanjun Huang, Chengbi Yu, Chenxi Li, Liangming Hu, Jixiong Xu","doi":"10.1016/j.xcrm.2025.102331","DOIUrl":"10.1016/j.xcrm.2025.102331","url":null,"abstract":"<p><p>Sodium-glucose cotransporter-2 inhibitors have been proposed as caloric restriction mimetics with potential anti-aging effects. However, clinical data on their influence on aging biomarkers are limited. In this multicenter, randomized, double-blind, placebo-controlled trial, 150 participants with type 2 diabetes are randomized (1:1) to receive oral henagliflozin (10 mg/day) or placebo for 26 weeks. Compared with placebo, henagliflozin significantly increases telomere length (primary endpoint), insulin-like growth factor-binding protein-3 levels, and β-hydroxybutyrate levels and improves glucose metabolism. Immune analysis reveals that henagliflozin significantly increases granzyme B expression in cytotoxic T lymphocytes (CTLs) and tends to increase perforin expression in CTLs and perforin and granzyme B expression in total T lymphocytes. Metabolomic analysis shows that henagliflozin induces changes in various metabolites, including increased thiamine levels and enhanced thiamine metabolism. These findings suggest that henagliflozin may exert anti-aging effects through multiple pathways. This study is registered at Chinese Clinical Trial Registry (ChiCTR2300068127).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102331"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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