In Silico and Experimental Evaluation of Myricetin in Insulin Resistance-Associated PCOS in Rats

Polycystic ovary syndrome (PCOS) is a prevalent endocrinal disease characterized by hyperandrogenism, insulin resistance, cardiometabolic dysfunction, and hormonal disturbances, often leading to infertility. IR, a hallmark feature of PCOS, is observed in 30%-95% of women with PCOS. Current therapies are associated with potential side effects, necessitating exploration of alternative strategies. The present study aimed to identify and evaluate natural phytoconstituents targeting insulin receptor substrate-1 (IRS-1), a critical mediator in insulin signaling. In silico molecular docking of 22 phytoconstituents against IRS-1 revealed myricetin (MYR) has a binding energy of -9.3 kcal/mol, and favorable ADMET characteristics. MYR also showed significant binding affinity against PI3K and NF-κB (-8.6 and -7.0 kcal/mol, respectively), indicating its potential to improve insulin sensitivity. Subsequently, the therapeutic efficacy of MYR was assessed in a high-fat diet and letrozole induced PCOS in rats. MYR treatment at varying doses significantly (p < 0.001) reversed PCOS associated with metabolic and reproductive abnormalities. MYR (300 mg/kg) demonstrated substantial improvements in body weight, BMI, estrous cycle, restored hormonal balance, and improved IR. MYR significantly improved β-cell functions, serum lipid profile, oxidative stress, and histology in ovarian tissues. The findings of the study underscore the potential of MYR as safe and effective candidate for PCOS management.