Small molecule selenium-based glutathione peroxidase 4 mimetic inhibits lipid peroxidation and protects cultured neurons from ferroptosis.

Glutathione peroxidases (GPXs) are a family of selenoenzymes that protect mammalian cells from oxidative damage by catalyzing the glutathione (GSH)-dependent reduction of peroxides. Among the eight human GPX isoforms (GPX1-8), GPX4 plays a critical role in suppressing ferroptosis, an iron-dependent, non-apoptotic form of cell death driven by the accumulation of lipid hydroperoxides. Ferroptosis has been implicated in the pathogenesis of various degenerative disorders, including neurodegenerative diseases. The development of GPX4 functional mimetics represents a promising strategy to prevent ferroptosis and its associated pathologies. Here, we report the design and synthesis of Compd. 5, a selenium-based small molecule that functionally mimics GPX4 activity. Compd. 5 robustly protects neurons from ferroptosis induced by diverse metabolic stressors, including GPX4 knockdown. Notably, Compd. 5 retains its anti-ferroptotic efficacy even under GSH-deficient conditions, highlighting its potential utility in contexts of impaired cellular GSH availability. Mechanistic studies demonstrate that Compd. 5 directly reduces HpETE-PE (hydroperoxy-eicosatetraenoyl-phosphatidylethanolamine), a key phospholipid hydroperoxide that drives ferroptosis, thereby closely recapitulating the ferroptosis-suppressive function of GPX4. This study provides compelling evidence that rationally designed GPX4 functional mimetics robustly suppress ferroptosis across diverse cell types under a broad spectrum of ferroptosis-inducing conditions. Thus, Compd. 5, a synthetic selenium-based small molecule with specific GPX4-like activity, represents a new class of anti-ferroptotic agents with significant translational potential for the treatment of neurodegenerative and other ferroptosis-driven diseases.