Galangin Mitigates Letrozole-Induced Polycystic Ovary Syndrome in Rats by Restoring PI3K/pAKT/PTEN Signaling

Purpose: Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder characterized by hyperandrogenism, ovulatory dysfunction, and the formation of ovarian cysts. Key contributors to its pathophysiology include oxidative stress, inflammation, and altered intracellular signaling, especially within the PI3K/pAKT/PTEN pathway. Galangin, a dietary flavonoid derived from Alpinia galanga , exhibits antioxidant, anti-inflammatory, and estrogen- modulatory properties. This study investigated the protective effects of galangin in a PCOS rat model induced by letrozole and explored its underlying molecular mechanisms. Methods: Thirty-six adult female Wistar rats were divided into six groups: control, galangin (8 mg/kg), letrozole (1 mg/kg), letrozole + galangin (4 or 8 mg/kg), and letrozole + metformin (20 mg/kg). All treatments were administered orally for 21 days. Serum hormones, oxidative stress biomarkers, inflammatory mediators, and key proteins in the PI3K/pAKT/PTEN pathway were assessed, along with histopathological and immunohistochemical analyses. Results: Letrozole administration induced characteristic PCOS-like features, including cystic follicle formation, hormonal imblanaces, oxidative stress, inflammation, and suppression of PI3K/pAKT signaling, accompanied by an increase in PTEN levels. Galangin pretreatment improved ovarian morphology, restored hormonal balance, reduced oxidative and inflammatory responses, and reactivated PI3K/pAKT signaling while downregulating PTEN. These effects were comparable to those observed with metformin. Conclusion: Galangin provides multidimensional protection against letrozole-induced ovarian dysfunction by alleviating oxidative stress, inflammation, and dysregulation of the PI3K/pAKT/PTEN pathway. These findings support the potential of galangin as a safe, multitarget natural adjunct for managing PCOS.