ATG9B identified as a direct functional target of liensinine in attenuating autophagic dysfunction and pathogenesis of KGN cell and polycystic ovary syndrome mice

Polycystic ovary syndrome (PCOS) is often associated with aberrant autophagy activation in granulosa cells, though the underlying mechanisms remain unclear. This study identified Autophagy-related protein 9B (ATG9B) as a key differentially expressed gene in PCOS granulosa cells through transcriptomic analysis of a public dataset. We demonstrated that ATG9B is significantly upregulated in PCOS and that its overexpression disrupts autophagy. Molecular docking and in vitro experiments revealed that the natural compound liensinine exerts a therapeutic effect by binding to ATG9B and subsequently modulating the AKT/mTOR signaling pathway. This action attenuates excessive autophagy and restores mitochondrial function in a DHT-induced PCOS cell model. Crucially, the therapeutic effects of liensinine were diminished upon ATG9B overexpression, confirming its central role. Our findings elucidate a novel mechanism by which liensinine targets ATG9B to regulate the AKT/mTOR axis and ameliorate aberrant autophagy, presenting a promising therapeutic strategy for PCOS. Summary This study elucidates the novel mechanism by which liensinine alleviates aberrant autophagy in PCOS by directly targeting ATG9B and modulating the AKT/mTOR signaling pathway, thereby advancing our understanding of autophagy dysregulation in PCOS and identifying a potential therapeutic target.