Hypothalamic RASA1 /Ras/ AKT / GnRH axis reprogramming mediates GLP ‐ 1RA 's central rescue of PCOS HPG dysfunction

Abstract Aim Polycystic ovary syndrome (PCOS), characterised by hyperandrogenaemia and hypothalamic–pituitary–gonadal (HPG) axis dysregulation driven by gonadotropin‐releasing hormone (GnRH) neuronal hyperactivity, remains mechanistically enigmatic, with limited targeted therapies. Although glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) show potential in alleviating PCOS reproductive dysfunction, their presumed mechanisms have been confined to peripheral metabolic modulation. Materials and Methods Using liraglutide as a representative GLP‐1RA, this study elucidated the central control mechanism mediating GLP‐1RA's therapeutic effects in PCOS through systematically scanning hypothalamic protein profiles combined with pharmacology gain‐/loss‐of‐function experiments. Results In letrozole‐induced PCOS rats, GLP‐1RA administration significantly reduced serum testosterone and luteinizing hormone levels, partially restored oestrous cyclicity, and ameliorated ovarian follicular abnormalities. Hypothalamic proteomic mapping revealed that GLP‐1RA counteracts hyperandrogenism‐induced signalling perturbations, with network analysis identifying RASA1 as the critical hub connecting therapeutic responses to GnRH regulation. Mechanistically, RASA1 exerts dual control over GnRH neurons—directly suppressing GnRH biosynthesis while modulating Ras/AKT signalling dynamics. Notably, hypothalamic RASA1's effect on regulating ovarian functions and hormone homeostasis was confirmed by an AAV‐based in vivo experiment. Crucially, genetic and pharmacological interventions (RASA1 overexpression/AKT inhibition vs. RASA1 knockdown/AKT activation) reciprocally mimicked testosterone‐induced GnRH hypersecretion and GLP‐1RA‐mediated GnRH suppression, respectively, establishing causal relationships within this signalling axis. Conclusion Our findings provide the first evidence of GLP‐1RA's central mechanism in PCOS management, positioning the hypothalamic RASA1/Ras/AKT/GnRH axis as a master regulator of HPG axis homeostasis and unveiling novel therapeutic targets for precision intervention in reproductive neuroendocrinology.