Melatonin protects against particulate matter-induced ovarian dysfunction by activating the Nrf2 signaling pathway to alleviate ferroptosis

Accumulating evidence suggests that exposure to ambient airborne PM2.5 increases the risk of primary ovarian insufficiency (POI). However, whether ferroptosis, a newly discovered type of cell death involved in PM2.5induced lung injury and fibrosis, is involved in PM2.5-induced POI has not been determined. This study aimed to verify the involvement of PM2.5-induced ferroptosis in ovarian dysfunction and further demonstrate that melatonin inhibits ferroptosis by activating the Nrf2 signaling pathway to ameliorate POI in vivo and in vitro. In our study, PM2.5 promoted iron accumulation and induced lipid peroxidation, thus contributing to ferroptosis in KGN cells and ovaries. However, these effects were eliminated and enhanced in Nrf2overexpressing and Nrf2-knockdown cells, respectively. In addition, melatonin and ferrostatin-1 (Fer-1) inhibited ferroptosis by activating the NRF2 signaling pathway, as evidenced by the silencing of Nrf2 in vivo and in vitro. Mechanistically, Nrf2-knockout mice were more susceptible to ferroptosis and PM2.5-induced POI than control mice. Moreover, melatonin suppressed changes in morphological and biochemical indicators related to ferroptosis, such as MDA and GSH depletion and GPX4 and XCT downregulation, by enhancing Nrf2 signaling. Here, we first reported that PM2.5 triggered ferroptosis by increasing ROS levels, lipid peroxidation and glutathione depletion. Notably, melatonin significantly decreased ferroptosis levels and improved ovarian function by activating the NRF2 signaling pathway in vivo and in vitro.