Drug Design, Development and Therapy (May 2025)
Semaglutide Alleviates Ovarian Oxidative Stress and Autophagy via the PI3K/AKT/mTOR Pathway in Mice with Polycystic Ovary Syndrome
Abstract
Sili Guo,* Xiaohan Li,* Mei Liu, Meiqi Feng, Xi Wang, Haibo Xue, Lei Zhang Department of Endocrinology and Metabolism, The First School of Clinical Medicine, Binzhou Medical University Hospital, Binzhou Medicial University, Binzhou, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Zhang, Department of Endocrinology and Metabolism, The First School of Clinical Medicine, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, People’s Republic of China, Email [email protected] Haibo Xue, Department of Endocrinology and Metabolism, The First School of Clinical Medicine, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, People’s Republic of China, Email [email protected]: Polycystic ovary syndrome (PCOS) is a typical reproductive endocrine system disease with high incidence rate among childbearing age women. Several clinical data show that glucagon-like peptide-1 receptor agonists (GLP-1RAs) might have therapeutic effects on PCOS, but the mechanisms are still unclear. Here, we aim to assess the effects of semaglutide (a weekly preparation of GLP-1RAs) on PCOS in vivo.Methods: C57BL/6J female mice aged 3 weeks were subcutaneously injected with dehydroepiandrosterone and fed high-fat diet for 3 weeks to establish PCOS model. Then, we randomly divided the modeled mice into PCOS group (n=6), S-Low group (n=6), and S-High group (n=6). Additionally, six normal mice served as controls. Mice in S-Low and S-High group were intraperitoneally injected with corresponding dose of semaglutide every week for 4 weeks. The estrus cycle was observed daily. At the end of the experiment, body weight, blood glucose, and serum hormone levels were measured. Ovarian morphology was also observed. Then, the oxidative stress markers, autophagy-related proteins and CYP19A1, StAR, and CYP17A1 expression in ovarian tissue were measured. Finally, we used Western blot to detect the expression of PI3K/AKT/mTOR and downstream proteins.Results: After treatment with semaglutide, the estrous rhythm of PCOS mice was restored, the number of ovarian vesicles decreased, serum hormone imbalance corrected, and glucose tolerance improved. The relative expression of CYP17A1, StAR, Beclin-1, and LC3B, as well as MDA, were significantly reduced, while CYP19A1, p62, GSH, and SOD were significantly increased. Finally, semaglutide alleviates ovarian oxidative stress and autophagy via the PI3K/AKT/mTOR pathway.Conclusion: Semaglutide alleviates autophagy and ovarian oxidative stress via the PI3K/AKT/mTOR pathway in mice with PCOS.Keywords: polycystic ovary syndrome, semaglutide, oxidative stress, autophagy
