Nrf2 suppresses erastin-induced ferroptosis through activating system Xc(-) in ovarian cancer

Background Ovarian cancer (OV) is a gynecologic tumor with high mortality due to its drug resistance. In most cases, simple standard care is not satisfactory. Ferroptosis as a non-apoptotic form of cell death may contribute to the selective elimination of certain tumor cells. Therefore, ferroptosis has been considered to be potential therapy in anti-tumor. Objective Here, we report that erastin inhibits OV cell viability by inducing ferroptosis and identified the ferroptosis resistance effect of Nrf2 in OV. Results We demonstrated that erastin-induced cells release more Fe2+, malondialdehyde (MDA), and less glutathione (GSH). Nevertheless, we found that erastin-induced ferroptosis in OV cells was inhibited by overexpressed Nrf2. Mechanistically, Nrf2 promotes system xc-, increases intracellular glutamate and GSH, and thus resists tumor ferroptosis. Specifically, Nrf2 promotes system XC mainly by increasing the expression of SLC7A11. Conclusion This study revealed a novel cancer-promoting mechanism of Nrf2, mainly enhanced ferroptosis resistance in OV.