Targeting IDO1 Suppresses RPE Ferroptosis and NLRP3 Inflammasome Activation and Ameliorates NaIO₃-Induced dry age-related macular degeneration

Background : Dry age-related macular degeneration (AMD) is a common chronic degenerative ocular disease for which no effective disease-modifying therapeutic options to date. Indoleamine 2,3-dioxygenase 1 (IDO1) has been reported to reshape cellular redox and metabolic states through ferroptosis; however, its potential involvement in the pathogenesis of dry AMD remains largely unexplored. Methods : Bioinformatic analysis identified IDO1 as a differentially expressed gene associated with dry AMD. IDO1 expression in retinal pigment epithelial (RPE) cells was silenced using siRNA or inhibited by the selective IDO1 inhibitor Epacadostat to evaluate ferroptosis. Transcriptome sequencing was performed to identify downstream signaling pathways, and NLRP3 overexpression was used for rescue experiments to verify the causal relationship. In vivo, a NaIO₃-induced retinal degeneration model was established, and Epacadostat was intravitreally injected. Retinal morphology (H&E staining, OCT, fundus photography, and autofluorescence) and function (ERG) were quantitatively assessed. Results : Both genetic and pharmacological inhibition of IDO1 significantly alleviated ferroptotic phenotypes and suppressed NLRP3 inflammasome activation in RPE cells. Overexpression of NLRP3 partially reversed the protective effects of IDO1 inhibition, suggesting that NLRP3 acts downstream of IDO1-dependent ferroptosis. In the NaIO₃-induced mouse model, Epacadostat treatment preserved retinal structure and improved retinal function. Conclusions : Targeting IDO1 effectively suppresses ferroptosis and inflammasome activation in RPE cells, providing dual structural and functional protection to the retina. These findings highlight IDO1 as a potential therapeutic target for dry AMD.