GNE-317 suppresses the progression of ovarian cancer by inducing ferroptosis through targeting GPX4

Abstract Ovarian cancer ranks among prevalent malignancies affecting the female reproductive system with an escalating incidence of drug resistance necessitating intensified efforts in drug discovery research for enhanced patient outcomes. Through rigorous screening within a small molecule compound library, we have pinpointed compound GNE-317 as a robust dual inhibitor targeting PI3K-mTOR via anticancer metabolic library screening methods. Our findings demonstrate that GNE-317 efficaciously impedes ovarian cancer cell proliferation while augmenting cellular demise relative to control groups. Notably, ferroptosis inhibitors exhibit potential in reversing GNE-317-induced cell death without impacting apoptosis or necrosis pathways. Further studies revealed that GNE-317 promoted the accumulation of lipid reactive oxygen species (ROS) and malondialdehyde (MDA). Mechanistically, GNE-317 directly binds to the GPX4, and the GNE-317-mediated increase in lipid ROS and MDA in OC were significantly reversed after GPX4 overexpression in ovarian cancer cells. Thus, GNE-317 can effectively inhibit ovarian cancer development, which may be achieved by increasing GPX4-mediated ferroptosis. These results suggest that GNE-317 has the potential to be a potential drug for targeted treatment of ovarian cancer.