iPLA2β Protects Retinal Pigment Epithelium From Ferroptosis in a Sodium Iodate-Induced Model of Dry AMD.

PURPOSE: Ferroptosis, characterized by lipid peroxidation, has been implicated in retinal pigment epithelium (RPE) degeneration in dry age-related macular degeneration (AMD). This study aimed to investigate the role of calcium-independent phospholipase A2 group VI (iPLA2β) in protecting RPE cells from oxidative stress using a sodium iodate (NaIO3)-induced dry AMD model.

METHODS

The iPLA2β knockout (KO) and wild-type (WT) mice were subjected to NaIO3 administration. Retinal structure and function were evaluated by histology and electroretinography. The involvement of ferroptosis was assessed by quantitative real-time polymerase chain reaction (qPCR) and Western blotting. Pharmacological intervention experiments used ferrostatin-1, α-tocopherol, and necrostatin-1s to evaluate protective effects. Western blotting was performed for RIP3 phosphorylation, and RIP3 KO mice were used to further assess necroptosis involvement.

RESULTS

The iPLA2β KO mice exhibited normal retinal morphology and function under baseline conditions. NaIO3 exposure caused pronounced RPE and photoreceptor degeneration, a characteristic downregulation of genes responsive to ferroptotic stress, elevated lipid peroxidation, and impaired visual function, which were markedly rescued by ferrostatin-1 and α-tocopherol, and partially by necrostatin-1s. NaIO3 did not induce RIP3 phosphorylation, and necrostatin-1s appeared to exert antioxidative effects. RIP3 KO mice developed severe RPE degeneration after NaIO3 exposure, significantly attenuated by necrostatin-1s. These findings indicate that lipid peroxidation-mediated ferroptosis, rather than necroptosis, is the primary mechanism of NaIO3-induced retinal degeneration, particularly at low doses of NaIO3.

CONCLUSIONS

The iPLA2β functions as a key suppressor of lipid peroxidation-mediated RPE degeneration in the NaIO3 model. Targeting ferroptosis-particularly via iPLA2β-may represent a potential therapeutic approach for protecting the RPE from oxidative stress-induced injury in dry AMD, although further validation in human tissues will be necessary.