Life sciences最新文献

{"title":"Aging-associated GSK3β overexpression exacerbates hepatic ischemia-reperfusion injury through Nrf2 deficiency-induced hepatocyte ferroptosis","authors":"You Wu ,&nbsp;Yan Zhang ,&nbsp;Shiwei Zhang ,&nbsp;Huahong Yang ,&nbsp;Xinxin Ci","doi":"10.1016/j.lfs.2026.124214","DOIUrl":"10.1016/j.lfs.2026.124214","url":null,"abstract":"<div><h3>Background and aims</h3><div>Aging can exacerbate hepatic ischemia-reperfusion injury (HIRI), but the underlying mechanisms remain uncertain. In this study, the mechanisms through which age-related dysregulation of the GSK3β-Nrf2 axis promotes hepatocyte ferroptosis and exacerbates HIRI were investigated.</div></div><div><h3>Methods</h3><div>We used a comparative approach to analyze the following: 1) human liver specimens from young (25–35 years) and elderly (65–75 years) donors; 2) young and aged C57BL/6 mice and Nrf2-knockout (Nrf2-KO) mouse models subjected to HIRI; and 3) radiation-induced senescent L02 hepatocytes. Key interventions included the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the GSK3β inhibitor lithium (LiCl).</div></div><div><h3>Results</h3><div>Our study revealed that aging leads to significant downregulation of Nrf2 in human livers, aged mice, and senescent hepatocytes. This suppression of age-related Nrf2 exacerbates HIRI, as reflected by impaired antioxidant defenses and increased ferroptosis (elevated lipid peroxidation, iron overload, malondialdehyde (MDA) accumulation, glutathione (GSH) depletion and TFR upregulation). Genetic Nrf2 deficiency exacerbates these pathological changes in both cellular and animal models. Notably, treatment with Fer-1 effectively reduced liver damage biomarkers (ALT/AST) and ferroptotic responses in Nrf2-knockout systems. Mechanistically, aging-induced GSK3β overexpression drives Nrf2 dysfunction, establishing a GSK3β-Nrf2-ferroptosis axis involved in IRI progression. Notably, therapeutic targeting of GSK3β by microdose lithium or ferroptosis inhibition by Fer-1 alleviated HIRI in aged mice.</div></div><div><h3>Conclusions</h3><div>Our study revealed a novel aging-related pathogenesis axis in which GSK3β upregulation drives Nrf2 deficiency-mediated ferroptosis in hepatocytes, thereby exacerbating HIRI. Pharmacological targeting of this pathway may be a promising therapeutic strategy for elderly patients undergoing liver surgery.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124214"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endostar overcomes Osimertinib-resistance mediated EGFR-activation mutation, T790M and cis-C797S triple mutations via enhancing the binding of Osimertinib to EGFR protein","authors":"Zhongquan Song ,&nbsp;Yanmei Zhu ,&nbsp;Surong Fang ,&nbsp;Shuhua Han","doi":"10.1016/j.lfs.2026.124218","DOIUrl":"10.1016/j.lfs.2026.124218","url":null,"abstract":"<div><h3>Aims</h3><div>The EGFR-C797S mutation is the main cause of Osimertinib resistance. No effective treatment regimen is currently available for patients harboring EGFR-activation mutation/T790M/cis-C797S triple mutations.</div></div><div><h3>Materials and methods</h3><div>Nine patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activation mutation/T790M/cis-C797S mutation were investigated. After Osimertinib resistance, these patients were treated with Endostar combination with Osimertinib. Network pharmacology and molecular dynamics simulations were used to clarify active sites of Endostar and the effect on protein conformation. <em>In vivo</em> and <em>in vitro</em>, EGFR L858R-T790M-C797S/H1975 cells were used to investigate the efficacy of co-treatment.</div></div><div><h3>Key findings</h3><div>Two patients achieved partial response (PR), six achieved stable disease (SD) and one had progressive disease (PD) at the 6-month efficacy assessment of co-treatment, resulting in an objective response rate (ORR) of 66.7% and a disease control rate (DCR) of 88.9%. These patients achieved a median progression-free survival (PFS) of 8.9 months and a median overall survival (OS) of 18.5 months, and no patients experienced grade III or IV adverse events. Endostatin, the active ingredient of Endostar, bound EGFR to “pseudo” mediate EGFR signaling pathway, and the introduction of Endostar enhanced the binding of Osimertinib to EGFR L858R/T790M/C797S protein. <em>In vitro</em> and <em>in vivo</em> experiments have found the co-treatment restored sensitivity to Osimertinib. Moreover, the combination therapy significantly inhibited the activation of the EGFR signaling pathway and tumor neovascularization.</div></div><div><h3>Significance</h3><div>This work demonstrated for the first time that Endostar enhanced the antitumor efficacy of Osimertinib, offering a potential therapeutic approach for patients harboring triple mutations.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124218"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Empagliflozin enhances neuroplasticity in rotenone-induced parkinsonism: Role of BDNF, CREB and Npas4” [Life Sci. 312 (1 January 2023) 121258]","authors":"Hager H. Mousa,&nbsp;Maha H. Sharawy,&nbsp;Manar A. Nader","doi":"10.1016/j.lfs.2026.124213","DOIUrl":"10.1016/j.lfs.2026.124213","url":null,"abstract":"","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124213"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minocycline-induced microglial remodeling restores hippocampal NMDA-dependent synaptic plasticity and reduces anxiety-like behavior in juvenile rats with temporal lobe epileptogenesis","authors":"Tatiana Y. Postnikova,&nbsp;Georgy P. Diespirov,&nbsp;Alexandra V. Griflyuk,&nbsp;Aleksey V. Zaitsev","doi":"10.1016/j.lfs.2026.124193","DOIUrl":"10.1016/j.lfs.2026.124193","url":null,"abstract":"<div><div>Microglial activation and neuroinflammation are recognized as key drivers of synaptic dysfunction in temporal lobe epilepsy (TLE), yet the causal mechanisms linking specific microglial phenotypes to neuronal hyperexcitability remain poorly understood, and clinically viable therapeutic strategies to modulate these processes are urgently needed. Using the lithium-pilocarpine model in young male rats (P21-P28), we demonstrate that a 7-day minocycline treatment (100 → 50 mg/kg, i.p.), initiated immediately following status epilepticus, induces robust and selective microglial morphological remodeling. Quantitative morphometric analysis of Iba1⁺ cells revealed a significant shift from activated amoeboid morphology to surveillant ramified phenotypes, without altering microglial density in hippocampal CA1 regions. This structural reorganization correlated with complete functional recovery: electrophysiological recordings showed full restoration of NMDA receptor-dependent long-term potentiation and rescue of NMDAR-mediated currents during high-frequency stimulation. Importantly, these synaptic improvements occurred independently of neuroprotection, as Nissl staining confirmed unchanged neuronal survival in CA1/CA3 subfields. Behavioral assessments at P27 demonstrated significant attenuation of epilepsy-associated anxiety-like behaviors, including reduced self-grooming and normalized exploratory activity in the open field test. Notably, minocycline treatment also attenuated reactive astrogliosis, suggesting coordinated modulation of neuroinflammatory cascades. Our findings demonstrate that short-term minocycline administration induces a structural and functional reprogramming of microglia, which is sufficient to restore hippocampal synaptic plasticity and reduce anxiety in a rat model of TLE. This highlights microglial morphological plasticity as a critical therapeutic target for counteracting epileptogenesis.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124193"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145944871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction notice to “Effectiveness of mesenchymal stem cell-seeded onto the 3D polylactic acid/polycaprolactone/hydroxyapatite scaffold on the radius bone defect in rat” [Life Sci. 257 (2020) 118038]","authors":"A. Oryan ,&nbsp;S. Hassanajili ,&nbsp;S. Sahvieh ,&nbsp;N. Azarpira","doi":"10.1016/j.lfs.2025.124146","DOIUrl":"10.1016/j.lfs.2025.124146","url":null,"abstract":"","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124146"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperglycemia disrupts alveolar bone homeostasis by inducing stem cell senescence through Mettl3/Foxo3/Sirt1 axis in diabetic periodontitis","authors":"Jie Zhou ,&nbsp;Xinyue Li ,&nbsp;Lanxi Xiao ,&nbsp;Yanlin Zhu ,&nbsp;Yuhan Yang ,&nbsp;Xiang Gao","doi":"10.1016/j.lfs.2026.124215","DOIUrl":"10.1016/j.lfs.2026.124215","url":null,"abstract":"<div><h3>Aims</h3><div>Diabetes exacerbates periodontitis by intensifying inflammatory responses and impairing tissue regeneration. Hyperglycemia-induced dysfunction of jawbone-derived bone marrow mesenchymal stem cells (BMSCs) contributes to the imbalance of bone remodeling and periodontal homeostasis. This study aimed to reveal the role and regulatory mechanism of stem cell senescence in diabetic periodontitis.</div></div><div><h3>Materials and methods</h3><div>Diabetic periodontitis model was established in mice by high-fat diet, streptozotocin injections and ligation. Following treatment with high glucose (HG) and <em>Porphyromonas gingivalis</em> lipopolysaccharide (Pg-LPS), BMSCs were analyzed for cellular senescence and m⁶A levels. Functional roles of Mettl3, Foxo3, and Sirt1 were explored by knockdown, overexpression, and pharmacological activation. MeRIP, ChIP, and RNA stability assays were employed to explore m⁶A-dependent Foxo3 degradation and its interaction with Sirt1. Therapeutic potential of Sirt1 activation was validated in vivo.</div></div><div><h3>Key findings</h3><div>Diabetic mice developed alveolar bone degeneration and cellular senescence pathway enrichment. HG + LPS co-stimulation induced BMSCs senescence, elevated m⁶A levels and Mettl3 expression. Mettl3 knockdown reduced senescence-associated secretory phenotypes. Mechanistically, m⁶A hypermodification on the Foxo3 coding sequence accelerated mRNA decay and impeded nuclear translocation via Ythdf2 recognition. Through its transcriptional regulation of Sirt1, Foxo3 mitigated senescence when overexpressed and exacerbated oxidative damage when knocked down. Sirt1 activation alleviated senescence in vitro and in vivo, reciprocally stabilizing Foxo3 and maintaining its transcriptional activity via deacetylation.</div></div><div><h3>Significance</h3><div>Hyperglycemia disrupts alveolar bone homeostasis by driving stem cell senescence through the Mettl3/Foxo3/Sirt1 axis, suggesting a promising therapeutic strategy for regenerative therapy under diabetic conditions.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124215"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cabozantinib induces NLRP3-CASP1-GSDMD-dependent pyroptosis in hepatocellular carcinoma","authors":"Li Lin ,&nbsp;Chiun Hsu ,&nbsp;Chia-Lang Hsu ,&nbsp;Cheng-Zhe Jian ,&nbsp;Zhi-Rui Feng ,&nbsp;Chih-Hung Chung ,&nbsp;Han-Ying Cheng ,&nbsp;Hsin-Yi Chang ,&nbsp;Ann-Lii Cheng ,&nbsp;Muh-Hwa Yang ,&nbsp;Da-Liang Ou","doi":"10.1016/j.lfs.2026.124210","DOIUrl":"10.1016/j.lfs.2026.124210","url":null,"abstract":"<div><h3>Aims</h3><div>Cabozantinib is a multi-target tyrosine kinase inhibitor approved for second-line treatment of advanced hepatocellular carcinoma (HCC). While its antiangiogenic and antiproliferative effects are well known, its immunomodulatory mechanisms remain incompletely understood. Here, we aimed to investigate the novel immunomodulatory mechanism of cabozantinib, focusing on its role in inducing pyroptotic cell death in HCC cells and myeloid-derived suppressor cells (MDSCs).</div></div><div><h3>Materials and methods</h3><div>Cabozantinib-induced pyroptosis was evaluated in HCC cell lines and MDSCs. The involvement of the canonical NLRP3–CASP1–GSDMD pathway was validated using MDSCs induced from <em>Nlrp3</em> knockout mice and <em>Gsdmd</em> knockout HCC cells. In vivo efficacy and immunomodulation were assessed using <em>Gsdmd</em> knockout Hepa1–6 tumors in immunocompetent mice, analyzed via flow cytometry, single-cell RNA sequencing, and phosphoproteomics.</div></div><div><h3>Key findings</h3><div>We show that cabozantinib induces pyroptotic cell death in both HCC cells and MDSCs via the canonical NLRP3–CASP1–GSDMD pathway. Disruption of this pathway using MDSCs induced from <em>Nlrp3</em> knockout mice or <em>Gsdmd</em> knockout HCC cells abrogated cabozantinib-induced pyroptosis. Critically, implantation of <em>Gsdmd</em> knockout tumors in vivo abolished the antitumor and immunomodulatory effects of cabozantinib, confirming the necessity of GSDMD-mediated pyroptosis. Furthermore, cabozantinib reduced MDSC accumulation and enhanced cytotoxic CD8⁺ T cell responses, findings further supported by phosphoproteomic analysis showing pyroptosis-associated signaling alterations.</div></div><div><h3>Significance</h3><div>These findings reveal a mechanistic link between cabozantinib-induced pyroptosis and immune activation. Our results provide a strong rationale for the clinical combination of cabozantinib with immunotherapy in the treatment of HCC.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124210"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adiponectin receptor agonist, AdipoRon, reduces the growth of prostate cancer cells and patient-derived organoids","authors":"Francielle C. Mosele ,&nbsp;Ana Luiza Romano Gabriel ,&nbsp;Nilton José dos Santos ,&nbsp;Caroline Nascimento Barquilha ,&nbsp;Caio Cesar Damasceno Monção ,&nbsp;Micheli Canuto de Lima ,&nbsp;Mark A. Rubin ,&nbsp;Sérgio Luis Felisbino ,&nbsp;Joanna Triscott","doi":"10.1016/j.lfs.2025.124175","DOIUrl":"10.1016/j.lfs.2025.124175","url":null,"abstract":"<div><div>Low adiponectin levels in obese men are associated with an incidence of aggressive prostate cancer (PCa). Despite significant advances in PCa treatment, some cases become resistant, making the development of new therapies crucial. An alternative treatment is the use of agonists, such as AdipoRon. Here, we elucidate the antitumor effects of AdipoRon on PCa models and demonstrate reduced cell proliferation, migration, and invasion in vitro. AdipoRon impaired mitochondrial respiration of androgen-dependent and castration-resistant cells. We show that this agonist reduces AR and PSA expression in androgen-dependent prostate cells. Adiponectin receptors (AdipoR1 and AdipoR2) were upregulated in PC3 and DU-145 cells. We hypothesize that the alteration of PPAR alpha could explain the effects of AdipoRon. Additionally, the antigrowth effects of AdipoRon were observed in the patient-derived organoids PM154 and MSK-PCa16. Our findings reveal that AdipoRon has strong in vitro antitumor effects on PCa, supporting its potential as a promising therapeutic candidate. Future studies should focus on in vivo models to validate these effects and explore the underlying mechanisms, which may open new therapies for PCa.</div></div><div><h3>Statement of implication</h3><div>AdipoRon decreases prostate cancer cell growth.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"387 ","pages":"Article 124175"},"PeriodicalIF":5.1,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen receptor–autophagy axis protects the heart, aorta and kidneys during perimenopausal aging: Evidence from human cohort and mouse experiments","authors":"Xiuting Xiang ,&nbsp;Weizhou Jiang ,&nbsp;Praneetha Palasuberniama ,&nbsp;M. Tanveer Hossain Parash ,&nbsp;Rahmawati Pare ,&nbsp;Yunjun Ruan","doi":"10.1016/j.lfs.2025.124183","DOIUrl":"10.1016/j.lfs.2025.124183","url":null,"abstract":"<div><h3>Aim</h3><div>The gradual decline in estrogen levels during perimenopause is strongly associated with an increased risk of metabolic and cardiovascular diseases. However, the specific relationship and underlying mechanisms remain incompletely understood. This study combines population data, network pharmacology, and mouse models to explore the detailed mechanisms underlying estrogen's organ-protective effects.</div></div><div><h3>Materials and methods</h3><div>We utilized data from the National Health and Nutrition Examination Survey (NHANES) to analyze the correlation between estradiol levels and conditions such as hypertension, kidney disease, diabetes, and hypercholesterolemia. A perimenopausal mouse model was established to assess the impact of estrogen replacement therapy on various organs, including the heart, aorta, and kidneys. Network pharmacology was used to identify molecular targets, and receptor-specific inhibitors along with autophagy inhibitors were applied for functional validation in estrogen-treated mice.</div></div><div><h3>Key findings</h3><div>Lower estradiol levels were significantly associated with an increased risk of hypertension, kidney disease, diabetes, and hypercholesterolemia. Estrogen treatment markedly reduced fibrosis in the heart, aorta, and kidneys, and promoted weight gain in mice, which mirrored BMI trends observed in human cohorts. Network pharmacology identified key molecular targets involved in estradiol-mediated pathways and mTOR-regulated autophagy. Functional validation confirmed that estrogen's protective effects depend on receptor activation and downstream autophagy signaling.</div></div><div><h3>Significance</h3><div>This study underscores the crucial role of the estrogen receptor-autophagy axis in metabolic regulation and organ protection during perimenopause. It provides new mechanistic insights that could inform precision hormone therapy strategies aimed at preventing aging-related diseases in women.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"387 ","pages":"Article 124183"},"PeriodicalIF":5.1,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABA induces myokine irisin release from skeletal muscle","authors":"Linling Fan ,&nbsp;Yijing Liao ,&nbsp;Zhihong Wang ,&nbsp;Yunzhi Ni ,&nbsp;Qiaoli Cui ,&nbsp;Yahao Wang ,&nbsp;Li Zhang ,&nbsp;Hongying Ye ,&nbsp;Xiaodong Sun ,&nbsp;Yiming Li ,&nbsp;Qinghua Wang","doi":"10.1016/j.lfs.2025.124181","DOIUrl":"10.1016/j.lfs.2025.124181","url":null,"abstract":"<div><h3>Introduction</h3><div>γ-Aminobutyric acid (GABA), a classical neurotransmitter, also regulates skeletal muscle-an endocrine organ secreting irisin. This FNDC5-derived myokine induces white adipose tissue browning, augmenting thermogenesis and metabolic function.</div></div><div><h3>Objectives</h3><div>This study investigated the effects of GABA on irisin secretion and its molecular mechanisms.</div></div><div><h3>Methods</h3><div>In L6 myotubes, GABA activated GABA_AR, causing membrane depolarization and calcium influx, which upregulated CREB phosphorylation and increased PGC-1α and FNDC5 expression, significantly elevating irisin secretion. In vivo, GABA treatment increased PGC-1α/FNDC5 expression in mouse skeletal muscle and raised serum irisin levels. Additionally, GABA-induced irisin promoted the browning of white adipose tissue by upregulating thermogenic genes and remodeling fat metabolism.</div></div><div><h3>Conclusion</h3><div>These findings reveal a novel role for GABA in regulating myokine secretion and suggest its potential as a therapeutic target for metabolic diseases such as obesity and type 2 diabetes.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"387 ","pages":"Article 124181"},"PeriodicalIF":5.1,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}