Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder characterized by hyperandrogenism and frequently associated with insulin resistance (IR), a key pathogenic factor in PCOS. However, insulin sensitizers commonly used to treat PCOS are often recommended off-label and may cause side effects. This study investigated the therapeutic effects of pancreastatin inhibitor 8 (PSTi8), an insulin sensitizer, in a PCOS rat model. The PCOS rat model was established by daily feeding with a high-fat diet and administering subcutaneous injections of dehydroepiandrosterone at a dose of 60 mg/kg body weight for 21 days and further, followed by 21 days of treatment with PSTi8 (10 mg/kg) and metformin (300 mg/kg). Body weight, estrous cycle, glucose, and insulin tolerance test results were monitored. Ovarian morphology, estrous cycle changes, oxidative stress and inflammatory markers, steroidogenic hormone levels and protein expression, and insulin signaling pathway were assessed to evaluate the therapeutic effectiveness of PSTi8 in PCOS rats. This study found that PSTi8 improved IR and reduced body weight in PCOS rats. PSTi8 lowered serum levels of insulin (27%), testosterone (56%), estradiol (2-fold), progesterone (21%), sex hormone-binding globulin (7.5%), and luteinizing hormone/follicle stimulating hormone ratio (57%). Additionally, PSTi8 helped to restore ovarian morphology, estrous cycle, and improve dyslipidemia. PSTi8 treatment also reduces the oxidative stress level of total superoxide ismutase (16%), glutathione peroxidase (26%), and inflammation in PCOS rats. Furthermore, PSTi8 restores the steroidogenic protein expression and increases PI3K/Akt phosphorylation in PCOS rats. These findings demonstrate PSTi8 exhibited comparable efficacy to metformin in ameliorating IR and ovarian dysfunction in the studied PCOS model. SIGNIFICANCE STATEMENT: Polycystic ovary syndrome (PCOS) increases risk of reproductive and metabolic disorders, partly due to systemic inflammation. This study combined dehydroepiandrosterone with high-fat diet and successfully induced PCOS-like features in rats. PSTi8, a pancreastatin inhibitor known for insulin-sensitizing effects in various disease models, effectively reversed PCOS-associated pathophysiology. PSTi8 improves insulin sensitivity by activating the PI3K/AKT signaling pathway and ameliorates oxidative stress and inflammation in PCOS rats. Additionally, PSTi8 treatment normalized steroidogenesis protein expression and reduced circulating biomarkers linked to cardiovascular risk.
