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

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.