O-GlcNAcylation stabilizes c-MYC to upregulate xCT and inhibit ferroptosis in ovarian cancer

AIMS: Ovarian cancer (OV) is one of the most prevalent and life-threatening malignancies among women worldwide. Resistance to conventional therapies poses a major challenge in OV treatment. Ferroptosis, a type of programmed cell death driven by iron accumulation and marked by lipid peroxidation, has garnered significant attention in cancer research. The regulation of ferroptosis involves intricate epigenetic, transcriptional, and post-translational modification (PTM) processes. O-GlcNAcylation, a reversible PTM occurring on serine/threonine hydroxyl groups of proteins, has been connected with the regulation of apoptosis, autophagy, and necroptosis. However, its role in ferroptosis is still poorly understood. MATERIALS AND METHODS: O-GlcNAcylation levels and ferroptosis-associated markers were compared between normal and OV tissues. OV cells were subjected to ferroptosis induction using Erastin or RSL3, while O-GlcNAcylation was modulated via the OGT inhibitor OSMI-1 or the OGA inhibitor Thiamet-G. Subsequent analyses were performed to assess ferroptotic phenotypes and the c-MYC/xCT/GSH/GPX4 signaling pathway. In vitro findings were validated using a nude mouse xenograft model. KEY FINDINGS: In this study, we observed elevated O-GlcNAcylation, higher protein levels of xCT, GPX4, and FTH1, as well as increased antioxidant capacity in ovarian cancer tissues compared with normal ovarian tissues. Modulating O-GlcNAcylation levels in OV cells revealed that its downregulation enhanced ferroptosis, whereas upregulation inhibited it. Further investigation revealed that c-MYC protein levels were regulated by O-GlcNAcylation. The O-GlcNAcylation-mediated stabilization of c-MYC led to increased xCT expression, thereby enhancing the xCT/GSH/GPX4 antioxidant axis and suppressing ferroptosis in OV. SIGNIFICANCE: Our research may provide intervention strategies for the treatment of OV.