Aims: Excessive oxidative stress is a major factor to damage retinal pigment epithelial (RPE) cells that promotes the development of retinal degeneration. We investigated the effects of 6dS, a pigment epithelium-derived factor (PEDF) derived factor on cultured RPE cells and retina of rats treated with sodium iodate (NaIO3). Methods: Annexin V/PI staining was used to determine ARPE-19 cell viability. FerroOrange and immunostaining of acrolein were used to detect intracellular labile ion (Fe2+)-dependent cell ferroptosis and lipid peroxidation reaction in plasma membrane. Immunoblotting and real-time qPCR were to investigate potential anti-ferroptosis signaling. Single intraperitoneal injection of NaIO3 (40 mg/kg) was performed in 8-week-old Sprague-Dawley male rats. Prior to NaIO3 injection, 6dS and vehicle eye drops were applied topically four times within an hour. PRE function was assessed at baseline ~ 2 weeks following NaIO3 injection and determined by immunostaining of the expression of PEDF, RPE65 and ZO-1.Retinal function, structure and subretinal drusen formation were assessed at baseline and 2 weeks by electroretinography (ERG) responses, H&E staining and retinal fundus angiography. Results: 6dS protected ARPE-19 cells against NaIO3-induced ferroptosis and lipid peroxidation. Also, 6dS induced the expression of anti-ferroptosis genes, including GPX-4, FTH1, xCT in cells response to NaIO3 stimulation. 6dS eye drop alleviated NaIO3-induced RPE dysfunction and acrolein expression. 6dS also reduced the impairments in retinal morphology and function and Drusen-like particles deposition. Conclusions: These findings indicate that the 6dS protects RPE cells against ferroptosis induced by NaIO3 and suggest that 6dS may be a potential candidate to treat atrophic AMD.