Diabetic retinopathy (DR) is a progressive microvascular complication of diabetes, and emerging evidence suggests that the retinal pigment epithelium (RPE), a key component of the outer blood–retinal barrier (BRB), plays an active role in the early pathogenesis of DR. Here, we investigated whether erythropoietin (EPO) could stabilize the outer BRB by preserving RPE junctional integrity and enhancing antioxidant responses, thereby mitigating early progression in DR. Intravitreal (IVT) administration of EPO in streptozotocin (STZ)-induced diabetic mice mitigated morphological disruption of the RPE and restored its barrier integrity, as assessed by transepithelial electrical resistance (TEER) measurements using primary marmoset RPE cells. EPO treatment attenuated oxidative damage in the RPE, as indicated by reduced accumulation of 4-HNE and nuclear localization of 8-OHdG, and simultaneously upregulated Nrf2 target genes, HO-1 and NQO1. EPO activated the AMPK–ULK1 axis, which enhanced autophagy and facilitated Keap1 degradation, thereby promoting Nrf2 nuclear translocation and subsequent activation of antioxidant responses. These findings suggest that EPO exerts cytoprotective effects through the integrated activation of autophagy and Nrf2-mediated antioxidant response in the diabetic RPE. Our results provide the therapeutic potential of EPO as a protective strategy targeting outer BRB impairment in early DR.
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