Alpha-Lipoic Acid and Saxagliptin Attenuate Ferroptosis-Related Ovarian Injury and Modulate FGF21/NOX4–NRF2/HO-1 Signaling in Letrozole-Induced Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder characterized by ovarian dysfunction, hormonal imbalance, and emerging ferroptosis-related abnormalities. This study investigated the effects of alpha-lipoic acid (ALA), saxagliptin (Saxa), and their combination in a letrozole-induced PCOS model, with focus on the ovarian FGF21/NOX4–NRF2/HO-1 and ferroptosis-related pathways. PCOS was induced in female rats by oral letrozole administration for 21 days. Rats were allocated into control, PCOS, ALA, Saxa, and ALA/Saxa groups, followed by 14 days of treatment. Body weight, ovarian index, ovarian histopathology, reproductive hormones, oxidative stress markers, ovarian FGF21 and NOX4 expression, NRF2/HO-1 signaling, and ferroptosis-related markers, including Fe+2, GPX4, and SLC7A11, were assessed. Letrozole induced weight gain, ovarian hypertrophy, follicular disruption, endocrine imbalance, and ferroptosis-related alterations, marked by increased ROS, MDA, Fe2+, and NOX4, alongside reduced FGF21, NRF2/HO-1, GPX4, and SLC7A11. ALA or Saxa attenuated these alterations, whereas ALA/Saxa produced greater improvements in ovarian morphology, hormonal status, redox homeostasis, and ferroptosis-related markers. These effects were associated with FGF21 upregulation, NOX4 suppression, enhanced NRF2/HO-1 signaling, and preservation of GPX4 and SLC7A11. In conclusion, ALA/Saxa therapy markedly ameliorated letrozole-induced PCOS in rats, accompanied by restoration of ovarian FGF21/NOX4 homeostasis, associated with enhancement of NRF2/HO-1 antioxidant responses, and attenuation of ferroptosis-related alterations.