Targeting ferroptosis in ocular diseases: mechanisms, clinical implications, and therapeutic horizons.

Abstract

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been increasingly implicated in selected ocular diseases, although its causal relevance varies across disease entities. The retina and retinal pigment epithelium are biologically susceptible to ferroptosis-related injury because of their high oxygen demand, abundant polyunsaturated lipids, mitochondrial activity, light exposure, and tightly regulated iron handling. This review summarizes core mechanisms of ocular ferroptosis, including iron uptake and export, glutathione-glutathione peroxidase 4 (GPX4)-dependent antioxidant defense, lipid peroxidation, mitochondrial dysfunction, neuroinflammation, and blood-retina barrier disruption. We discuss evidence from major degenerative, vascular, ischemic, hereditary, infectious, and immune-mediated retinal diseases, with particular attention to glaucoma, age-related macular degeneration, diabetic retinopathy, ocular toxoplasmosis, uveitis, retinal vasculitis, and inflammatory chorioretinopathy. We also evaluate ferroptosis-targeted therapeutic strategies, proposed operational criteria for defining ferroptosis in retinal disease, and candidate structural, functional, biochemical, and imaging endpoints for future translational studies. Current evidence supports ferroptosis as a context-dependent contributor to retinal injury rather than a uniform pathogenic mechanism. Future studies should integrate cell-type-resolved biomarkers, lipidomic and imaging readouts, functional rescue experiments, and clinically meaningful visual outcomes to clarify when ferroptosis modulation may support vision preservation.