Background: Insulin-resistant polycystic ovary syndrome (IR-PCOS) is a refractory endocrine disorder with limited therapeutic options. Wogonin, a natural flavonoid compound, has shown potential therapeutic efficacy; however, its underlying mechanism remains unclear. This study aimed to explore the therapeutic effects of wogonin on IR-PCOS and the mechanistic involvement of fibronectin 1 (FN1) and phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (AKT) signaling pathway.

Methods: The interaction between wogonin and its potential target was predicted using molecular docking. An IR-PCOS mouse model was treated with wogonin alone or in combination with tail-vein injection of shFN1 or short hairpin negative control (shNC) lentiviral particles. Metabolic parameters, sex hormones, ovarian morphology, and key pathway proteins were assessed using glucose/insulin tolerance tests, enzyme-linked immunosorbent assays (ELISA), histopathology, and Western blotting.

Results: Molecular docking demonstrated a stable binding between wogonin and FN1. In IR-PCOS mice, wogonin significantly reduced body weight, restored serum sex hormone imbalances—characterized by decreased testosterone, estradiol, luteinizing hormone (LH), and the LH/follicle-stimulating hormone (FSH) ratio alongside increased progesterone—and improved glucose metabolism and insulin sensitivity. It also normalized ovarian morphology, reduced cystic follicles, promoted follicular development, and inhibited granulosa cell apoptosis. Mechanistically, wogonin modulated the insulin signaling pathway and activated the FN1/PI3K/AKT pathway in ovarian tissues. Notably, these therapeutic effects of wogonin were substantially reversed by shFN1.

Conclusion: Wogonin exerts comprehensive therapeutic effects against IR-PCOS by targeting FN1 to activate the PI3K/AKT pathway, identifying FN1 as a key mechanistic target.