CUEDC2 improves pyroptosis and kidney damage in diabetic kidney disease by inhibiting NLRP3 inflammasome activation

Diabetic kidney disease (DKD) is highly prevalent worldwide, and its incidence continues to rise annually. Hyperglycemia, fatty acids, and other damage-related molecules are detected by specific pattern recognition receptors (PRRs), thereby triggering pyroptosis, leading to kidney damage and functional decline. However, the main pathways and underlying mechanisms remain unclear. Here, we confirm that the pyroptosis signal transduction pathway is intimately associated with the pathogenesis of DKD. Furthermore, CUEDC2, a protein involved in cell cycle, cellular stress response, inflammatory response, and tumorigenesis and regulation, was found to be downregulated in the kidneys of DKD mice and exhibited a negative correlation with glomerular endothelial cell (GEC) injury and pyroptosis. In the GEC pyroptosis model, inhibition of CUEDC2 expression facilitated the activation of the NLRP3 inflammasome, exacerbating pyroptosis. Conversely, CUEDC2 overexpression inhibited NLRP3 inflammasome activation, thereby improving pyroptosis. CUEDC2 exerted a protective effect by attenuating lipo polysaccharide-induced NLRP3 inflammasome activation and pyroptosis. Mechanistically, CUEDC2 interacted with NLRP3 during inflammasome activation, thereby inhibiting IL-1β maturation and caspase-1 activation. This study provides a new mechanism underlying the progression of DKD and identifies CUEDC2 as a potential therapeutic target.