Scutellarin ameliorates PCOS mouse model by restoring mitochondrial function and inhibiting granulosa cell apoptosis

BACKGROUND: Polycystic ovary syndrome (PCOS), a common endocrine-metabolic disorder, lacks effective therapeutic options. Granulosa cell (GC) apoptosis and mitochondrial dysfunction are critical drivers of ovarian dysfunction in PCOS, yet targeted therapies are scarce. Scutellarin, a bioactive flavonoid, is a promising but unexplored candidate for treating PCOS. METHODS: We investigated scutellarin's effects in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model and in DHEA-treated human granulosa-like KGN cells. We assessed metabolic and reproductive parameters, ovarian histology, and fertility, and examined molecular mechanisms using transcriptomics, qRT-PCR, and Western blotting. Apoptosis and mitochondrial function were evaluated via TUNEL staining, flow cytometry, and real-time mitochondrial assays. RESULTS: Scutellarin treatment was associated with improved metabolic phenotypes in PCOS mice, including glucose intolerance and insulin resistance, a normalized estrous cycle, lower serum testosterone and LH levels, better ovarian morphology, and enhanced fertility. Mechanistically, scutellarin correlated with reduced ovarian GC apoptosis and modulation of BCL2, BAX, and cleaved Caspase-3. Transcriptomic analysis identified the PI3K/Akt signaling pathway as a key mediator, and scutellarin dampened its abnormal activation in DHEA-induced PCOS in vivo and in vitro. Furthermore, scutellarin was associated with improved mitochondrial function in DHEA-treated KGN cells, evidenced by reduced ROS production and restored membrane potential. CONCLUSION: Scutellarin is associated with the amelioration of metabolic and reproductive abnormalities in a PCOS mouse model, correlating with reduced GC apoptosis and improved mitochondrial function. By modulating these cellular defects, scutellarin offers potential dual benefits on ovarian and systemic dysfunctions, highlighting its value for clinical investigation and providing novel mechanistic insights.