A PEDF-Derived Short Peptide Prevents Sodium Iodate-Induced Retinal Degeneration in Rats by Activating the SLC7A11/GSH/GPX4 Pathway in the RPE Cells.

Retinal pigment epithelial (RPE) cell damage caused by oxidative stress is a key factor in the pathogenesis of dry age-related macular degeneration (AMD). 6dS peptide is derived from the neuroprotective motif of pigment epithelium-derived factor (PEDF) and has antioxidant effects. This study used the sodium iodate (SI, a chemical oxidant)-induced animal dry AMD model to investigate the 6dS-mediated antioxidant mechanism. 6dS reduced SI-induced cytotoxicity, including ferrous iron accumulation, lipid peroxidation, glutathione (GSH) depletion, and ferroptosis in ARPE-19 cells. SI injection in rats induced cell death and lipid peroxidation in the RPE layer, along with retinal atrophy and electrophysiological dysfunction, recapitulating features of dry AMD that were counteracted by 6dS eye drop treatment. Mechanistically, 6dS induced the expression of SLC7A11 (solute carrier family seven member 11) and glutathione peroxidase 4 (GPX4) to alleviate SI-induced GSH depletion and lipid peroxidation. Inhibitors targeting the PEDF receptor, SLC7A11, and GPX4 abolished the 6dS effect. Our study proposes an antioxidant mechanism through which PEDF receptor signalling links to the SLC7A11/GSH/GPX4 axis to alleviate intracellular redox imbalance. These findings suggest that 6dS eye drops may be a promising treatment for dry AMD.