Nrf2-ARE signaling pathway as a key regulator of oxidative stress and antioxidant responses in granulosa cells in polycystic ovary syndrome

Objective: Polycystic ovary syndrome (PCOS) is a metabolic and endocrine disorder that frequently results in infertility due to ovulatory dysfunction. Granulosa cells (GCs), which are essential for oocyte maturation, are highly vulnerable to oxidative stress (OS)-induced damage. The nuclear factor erythroid-2-related factor 2 (NRF2)-antioxidant responsive element (ARE) pathway, a major antioxidant mechanism, may help protect GCs from OS. This study investigated NRF2-ARE pathway activity in GCs of PCOS patients compared to healthy fertile controls. Methods: In total, 46 follicular fluid and GC samples were collected from 28 patients diagnosed with PCOS and 18 fertile women aged 20-40 years. After RNA extraction, expression levels of antioxidant genes- heme oxygenase 1 (HO1), peroxiredoxin 1 (PRDX1), superoxide dismutase 1 (SOD1), thioredoxin (TXN), NRF2, and kelch like ECH associated protein 1 (KEAP1)-were measured using quantitative reverse transcription polymerase chain reaction. In addition, total antioxidant capacity (TAC) and nitric oxide (NO) levels were analyzed in follicular fluid, with statistical comparisons performed using the t-test. Results: In GCs of PCOS patients, HO1 expression was downregulated, while PRDX1, SOD1, NRF2, TXN, and KEAP1 were upregulated. NO activity was elevated, and TAC levels were significantly decreased in the follicular fluid of PCOS patients. Conclusion: These findings demonstrate a significant association between antioxidant gene expression in GCs and PCOS. The results suggest that OS plays a critical role in the development and progression of PCOS.