A prospective therapeutic strategy: GPX4-targeted ferroptosis mediators.

As a crucial regulator of oxidative homeostasis, seleno-protein glutathione peroxidase 4 (GPX4) represents the primary defense system against ferroptosis, making it a promising target with important clinical application prospects. From the discovery of covalent and allosteric sites in GPX4, substantial advancements in GPX4-targeted small molecules have been made through diverse discovery and design strategies in recent years. Moreover, as an emerging hotspot in drug development, seleno-organic compounds can functionally mimic GPX4 to reduce hydroperoxides. To facilitate the further development of selective ferroptosis mediators as potential pharmaceutical agents, this review comprehensively covers all GPX4-targeted small molecules, including inhibitors, degraders, and activators. In addition, seleno-organic compounds as GPX mimics are also included. We also provide perspectives regarding challenges and future research directions in this field.
Competing Interests: Declaration of competing interest All authors declare that they have no competing financial interests or personal relationships that could affect the work reported in the paper.
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