O-GlcNAcylation Stabilizes NEK7 to Drive Podocyte Pyroptosis in Diabetic Kidney Disease

We identify threonine 302 as the critical O-GlcNAcylation site on NIMA-related kinase 7 (NEK7), which stabilizes NEK7 by inhibiting its proteasomal degradation, thereby enhancing NLRP3 inflammasome activation and podocyte pyroptosis in diabetic kidney disease (DKD). Chronic hyperglycemia activates the hexosamine biosynthetic pathway (HBP), driving pathological O-GlcNAcylation and significant upregulation of NEK7, O-GlcNAc transferase, and glutamine fructose-6-phosphate amidotransferase 1 in glomeruli from patients with DKD and experimental models. This study establishes the discovery of the pathogenic glucose/O-GlcNAc/NEK7/NLRP3 signaling axis, identifying a novel posttranslational mechanism driving podocyte loss in DKD progression. Pharmacological inhibition of the HBP with 6-diazo-5-oxo-l-norleucine normalizes O-GlcNAcylation, suppresses NEK7-driven pyroptosis, and mitigates renal injury, demonstrating the therapeutic potential of targeting threonine 302, NEK7, or the HBP for DKD management.