Modulatory effect of quercetin on premature ovarian insufficiency induced by cyclophosphamide via the PARP1 and GSK3β

Premature ovarian insufficiency (POI) is a significant side effect of cyclophosphamide (CTX) chemotherapy in women, leading to early ovarian dysfunction. Quercetin (QR), a flavonoid with antioxidant and anti-apoptotic properties, has shown potential in mitigating ovarian damage. This study aimed to investigate the molecular pharmacological mechanisms underlying QR's protective effects against POI using network pharmacology, molecular docking, and in vivo experimental models. Network pharmacology and molecular docking were first employed to identify the core targets of QR in ameliorating POI. Subsequently, histopathological analysis (HE and Masson staining), hormone level assessment, and protein expression analysis (via TUNEL, immunofluorescence, and immunohistochemistry) were performed to evaluate QR's therapeutic impact. The results demonstrated that QR intervention significantly increased serum levels of AMH, E2, and SOD in POI rats, while reducing FSH, LH, and MDA levels. Furthermore, QR treatment decreased Bax expression, enhanced Bcl-2 expression, and elevated Caspase-3 activity, indicating a reduction in ovarian cell apoptosis. Mechanistically, QR improved ovarian function by inhibiting PARP1 expression and GSK3β activity, attenuating oxidative stress and cellular senescence. These findings suggest that QR exerts protective effects on ovarian function through multiple interconnected molecular pathways, making it a potential therapeutic candidate for managing POI.