Lycopene Ameliorates Polycystic Ovary Syndrome in Rats by Inhibiting Ovarian Ferroptosis Through Activation of the AMPK/Nrf2 Pathway

ABSTRACT Lycopene (LYC) is an extremely powerful antioxidant with the potential to treat a range of diseases and to inhibit ferroptosis. This research aims to elucidate how LYC impacts polycystic ovarian syndrome (PCOS) and the action mechanisms. A PCOS rat model was constructed by injecting DHEA. Different doses of LYC were injected intraperitoneally in PCOS rats, the estrous cycle was recorded. The histopathological damage of ovary in PCOS rats was observed by HE staining, testosterone (T), estradiol (E2), luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were examined by ELISA kits. Transmission electron microscopy, prussian blue staining, biochemical kits to determine ferroptosis. Immunohistochemistry and Western blot to assess the levels of ferroptosis‐related and AMPK/Nrf2 pathway‐related proteins to explore whether LYC affects ferroptosis in PCOS through this pathway. PCOS rats had significantly higher body weights, ovarian weights and ovarian indices, and disorganized estrous cycles, which were dose‐dependently ameliorated by LYC. In addition, LYC significantly ameliorated the histopathological damage of ovary in PCOS rats and restored the normal secretion of T, E2, LH, and FSH. LYC attenuates iron deposition in PCOS ovarian tissues, reduces iron and ROS levels, and inhibits ferroptosis. Notably, LYC activated the AMPK/Nrf2 pathway, and AMPK inhibitor intervention attenuated the therapeutic effect of LYC in PCOS rats, suggesting that LYC acts through the AMPK/Nrf2 pathway. LYC attenuates estrous cycle disruption, ameliorates pathological impairments, and inhibits ferroptosis in PCOS rats by modulating the AMPK/Nrf2 pathway.