Ezetimibe attenuates diabetic retinopathy via NRF2-mediated suppression of inflammation and oxidative stress

Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults, driven by chronic inflammation and oxidative stress. Ezetimibe (EZE), a lipid-lowering agent, has been shown to activate the NRF2 pathway, but its role in DR remains unexplored. Our study utilized in vitro and in vivo models to investigate the protective effects of EZE on diabetic retinopathy (DR).

ARPE-19 cells were exposed to high glucose (HG, 25 mM) with or without EZE (5-20 μM) and/or ML385 (NRF2 inhibitor). NRF2 nuclear translocation, mitochondrial ROS (mtROS), and inflammatory mediators were assessed by Western blot, Immunofluorescence analysis, qPCR, and flow cytometry. In vivo, streptozotocin-induced diabetic wild-type (WT) and NRF2 knockout (Nrf2 KO) mice were treated with EZE (2 or 10 mg/kg/day) for 4 weeks. Retinal inflammation and structural integrity were evaluated by Western blot, H&E staining, and immunohistochemistry.

EZE dose-dependently promoted NRF2 nuclear translocation and reduced HG-induced mtROS, NF-κB activation, and expression of TNF-α, IL-6, MCP-1, COX-2, iNOS, and VEGFA in ARPE-19 cells. These effects were abolished by ML385. In WT diabetic mice, EZE improved fasting glucose, preserved retinal layer thickness, and reduced retinal inflammation. In contrast, EZE failed to exert protective effects in Nrf2 KO mice.

EZE exerts retinal protection in DR via NRF2-mediated suppression of oxidative stress and inflammation. These findings support the potential repurposing of EZE as a safe intervention for DR.