Inhibition of Cullin3 Neddylation Alleviates Diabetic Retinopathy by Activating Nrf2 Signaling to Combat ROS-Induced Oxidative Stress and Inflammation

Oxidative stress and inflammation induced by reactive oxygen species (ROS) play important roles in the development of diabetic retinopathy (DR). Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which is negatively controlled by Cullin3-RING E3 ligase (CRL3) and controls ROS levels, is compromised in DR. CRL3 activity is regulated by Cullin3 neddylation. Nonetheless, the relationship between Cullin3 neddylation and DR remains uncertain. The goal of this study was to evaluate the effect of Cullin3 neddylation on DR and its underlying mechanisms by utilizing MLN4924, a neddylation inhibitor. Cullin3 neddylation was elevated in diabetic rats' retinas as well as in advanced glycation end products (AGEs)-induced endothelial cells. Inhibiting neddylation of Cullin3 with MLN4924 downregulated Nrf2 ubiquitination, promoted Nrf2 accumulation, suppressed ROS-induced oxidative stress and inflammation, and attenuated blood-retinal barrier (BRB) breakdown in both diabetic vivo and vitro models. However, the beneficial impact of MLN4924 was compromised when Nrf2 was suppressed with siRNA in vitro. This study showed that inhibition of Cullin3 neddylation with MLN4924 exerted protective effect on DR by activating Nrf2 signaling to inhibit ROS-induced retinal injury, which indicated that targeting Cullin3 neddylation could be a promising treatment option for DR.