MCC950 targets the ROS-NEK7-NLRP3 axis to improve type 2 diabetic retinopathy

Globally, type 2 diabetes mellitus (T2DM) constitutes more than 90% of all diabetes cases, with diabetic retinopathy (DR) emerging as the predominant microvascular complication, resulting in vision loss in roughly 30% of affected individuals ^[1] . In contrast to type 1 diabetes, DR associated with T2DM is marked by insulin resistance and persistent low-grade inflammation, which may intensify the activation of the NLRP3 inflammasome ^[2] . The pathogenesis of diabetic retinopathy is fundamentally driven by the activation of the NLRP3 inflammasome due to redox disequilibrium ^[3] .In this study, we elucidate a novel mechanism through which MCC950, a selective inhibitor of NLRP3, mitigates DR via the ROS-NEK7-NLRP3 pathway. Diabetic rats induced by streptozotocin were administered intravitreal injections of MCC950 at varying concentrations (0.01, 0.1, 1, 10 mM). Quantitative assessments revealed that a concentration of 1 mM MCC950 markedly improved retinal histopathological alterations (p < 0.05) and modulated retinal apoptosis and oxidative stress to a considerable degree (p < 0.05). On a mechanistic level, MCC950 suppressed NLRP3 inflammasome activation (manifested by reduced levels of Cleaved Caspase-1, IL-1β, and IL-18, p < 0.001) in a dose-dependent manner by disrupting the interaction between NEK7 and NLRP3. Notably, there was a strong positive correlation between the intensity of ROS fluorescence and the fluorescence expression of NEK7 (r = 0.8857, p < 0.05), with MCC950 treatment significantly lowering retinal ROS levels at the 1 mM concentration. Moreover, pharmacological inhibition of NEK7 potentiated the therapeutic efficacy of MCC950. This research establishes the upregulation of NEK7 mediated by ROS as a critical factor in NLRP3 activation in DR, and provides pioneering evidence for the efficacy of dose-optimized MCC950 therapy targeting this axis.