Ferroptosis in autoimmune uveitis: potential links to blood–retinal barrier dysfunction and retinal inflammation
TL;DR
This Mini Review examines ferroptosis as a potential contributor to BRB dysfunction and retinal inflammation and separates direct AU/EAU findings from extrapolated evidence and highlights priorities for preclinical validation.
Abstract
Autoimmune uveitis (AU) is a vision-threatening intraocular inflammatory disease characterized by disruption of ocular immune privilege, blood-retinal barrier (BRB) dysfunction, and progressive immune-mediated retinal injury. Although corticosteroids and conventional immunosuppressive therapies remain clinically effective, their long-term use is limited by adverse effects, relapse, and incomplete disease control. Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation. It may provide a mechanistic link between oxidative stress, retinal cell injury, and inflammatory amplification. The retina is potentially susceptible because of its high oxygen demand, redox-active iron, and enrichment in polyunsaturated fatty acids. Direct evidence in AU, however, remains limited. In experimental autoimmune uveitis (EAU), fine particulate matter with an aerodynamic diameter of 2.5 μm or less (PM2.5) induced ferroptosis-related changes in CD4+ T cells and enhanced T helper 17 (Th17) pathogenicity, whereas modulation of transforming growth factor-β receptor 1 (TGFBR1) altered the glutathione peroxidase 4 (GPX4)/cystine–glutamate antiporter (xCT) axis, lipid peroxidation, and inflammatory severity. Studies in retinal pigment epithelial cells, retinal vascular endothelial cells, and other retinal injury models provide supporting evidence but should not be interpreted as direct proof in AU. This Mini Review examines ferroptosis as a potential contributor to BRB dysfunction and retinal inflammation. It separates direct AU/EAU findings from extrapolated evidence and highlights priorities for preclinical validation.