Decoding GPX4 regulation in ferroptosis: mechanisms and therapeutic implications

Ferroptosis, a regulated form of cell death, is determined by iron-dependent lipid peroxidation. A selenoenzyme called glutathione peroxidase 4 (GPX4) detoxifies phospholipid hydroperoxides at the heart of this process. As the pivotal gatekeeper of ferroptosis, GPX4 is implicated in a wide range of pathologies, including cancer, neurodegeneration, acute renal failure, and infection. In this review, we discuss how GPX4 transcription and mRNA stability are controlled by transcription factors, epigenetic modifications, and noncoding RNAs and how GPX4 degradation and activity are modulated by post-translational modifications, including ubiquitination, phosphorylation, palmitoylation, methylation, hydroxylation, and lactylation. We also summarize new therapeutic methods targeting GPX4, namely the ferroptosis inducers for cancer therapy and ferroptosis inhibitors that prevent ferroptosis-related damage.