A targetable OSGIN1 AMPK SLC2A3 axis controls the vulnerability of ovarian cancer to ferroptosis

Currently, there are no effective treatments for ovarian cancer. Recent studies suggest that ferroptosis-targeted drugs represent a promising approach for the treatment of ovarian tumors. However, this approach has not been translated into an effective therapy. Oxidative stress-induced growth inhibitor 1 (OSGIN1), which is a tumor suppressor gene known to regulate the cellular stress response and apoptosis, is associated with ovarian cancer development. However, the underlying mechanisms involved in ferroptosis regulation have not been elucidated. Thus, this study aimed to investigate the effect and underlying regulatory mechanism of the OSGIN1 gene on ovarian cancer cells. The present study demonstrated that loss of the OSGIN1 gene promoted ovarian cancer growth and conferred resistance to drug-induced ferroptosis. Mechanistically, the loss of OSGIN1 activates AMPK signaling through ATM, leading to the upregulation of SLC2A3, which protects cells from ferroptosis and renders them insensitive to ferroptosis inducers. Notably, an SLC2A3-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on ovarian cancer patient-derived xenograft tumors. Our results demonstrated that the loss of the OSGIN1 gene enhanced the progression of ovarian cancer and protected ovarian cancer cells against drug-induced ferroptosis through the AMPK-mediated transcription of SLC2A3. Overall, anti-SLC2A3 therapy is a promising method to improve ovarian cancer treatment by targeting ferroptosis.