Targeting glutathione peroxidase 4 in ferroptosis: from immune regulation to pharmacological development and translational applications.

Glutathione peroxidase 4 (GPX4) is a selenocysteine (Sec)-containing antioxidant enzyme and the only known mammalian enzyme capable of directly reducing membrane-embedded phospholipid and cholesterol hydroperoxides. It is recognized as a central regulator of ferroptosis, modulating cellular redox balance and influencing cell fate under oxidative stress. Despite a decade of research, critical gaps remain. Existing reviews largely focus on isolated diseases or single targeting strategies, and few provide an integrated framework that spans molecular regulation, physiological function, and clinical translation. The regulatory networks that control GPX4, from transcription to post-translational modifications and protein interactions, remain incompletely defined, and its ferroptosis-independent functions are underexplored. Moreover, the context-dependent and bidirectional roles of GPX4 across different diseases have not been systematically analyzed to guide appropriate therapeutic strategies. To address these gaps, this review delineates the structural basis and isoform-specific functions of GPX4, maps its multilayered regulatory network, and defines its roles across key physiological and pathological processes, including cancer, neurodegeneration, ischemia-reperfusion (I/R) injury, and autoimmune diseases. We also evaluate GPX4-targeted chemical strategies and analyze four core translational barriers: target specificity, systemic toxicity, acquired resistance, and tissue delivery, with evidence-based solutions for each. We conclude by identifying unresolved mechanistic questions and outlining priorities to accelerate clinical translation.