Polycystic ovary syndrome (PCOS) is a multifaceted endocrine disorder affecting 5–20 % of reproductive-aged women, characterized by hyperandrogenism, ovulatory dysfunction, insulin resistance, and chronic low-grade inflammation. This study investigates the therapeutic potential of chlorogenic acid (CGA), a bioactive polyphenol abundant with anti-inflammatory and antioxidant properties, in a letrozole (LZ)-induced PCOS mouse model.

Forty-eight adult female mice were divided into four groups (n = 12): control, PCOS-induced (animals received daily oral administration of letrozole at 4 mg/kg/day for 21 days), PCOS-induced + CGA 50 mg/kg/day (PCOS-induced mice treated with chlorogenic acid at 50 mg/kg/day for 14 consecutive days), and PCOS-induced + CGA 100 mg/kg/day (PCOS-induced mice treated with chlorogenic acid at 100 mg/kg/day for 14 consecutive days). At the end of the experimental period, blood samples and ovarian tissues were collected from all groups for biochemical, molecular, and histopathological analyses.

LZ-induced PCOS disrupted sex hormone profiles, causing hyperglycemia and elevated insulin resistance, alongside NLR family pyrin domain containing inflammasome (NLRP3) activation and nuclear factor erythroid 2–related factor 2 p65 (NF-κB p65) / Interleukin-1β (IL-1β) upregulation, driving chronic inflammation. Oxidative stress was evident through impaired Nrf2 activity, regulated by the Phosphoinositide 3-kinase (PI3K)/protein kinase B (PI3K/AKT) pathway. CGA treatment mitigated these pathological changes by enhancing ovarian Nrf2 mRNA expression, suppressing PI3K/AKT signaling, and attenuating inflammatory responses through downregulation of the NLRP3/NF-κB p65/IL-1β axis and pro-inflammatory cytokine production.

CGA mitigates LZ-induced PCOS through the dual mechanism of modulating the PI3K/AKT-Nrf2 antioxidant defense mechanism and suppression of the NLRP3 inflammasome/NF-κB p65/IL-1β inflammatory pathway.