NUAK1 promotes diabetic kidney disease by accelerating renal tubular senescence via the ROS/p53 axis

<p dir="ltr">Diabetic kidney disease (DKD) progression involves intricate interactions among senescence, oxidative stress, inflammation, and fibrosis. This study systematically investigates the regulatory role and molecular mechanisms of NUAK1 in DKD pathogenesis. Bioinformatics analysis of GEO datasets identified NUAK1 as a differentially expressed gene, validated in HK-2 cells, high-fat diet/streptozotocin (HFD/STZ)-induced DKD mice, D-galactose (D-gal)-induced senescent mice and human peripheral blood mononuclear cells (PBMCs). Functional studies demonstrated that NUAK1 inhibition via siRNA knockdown, pharmacological inhibitors, or kidney tubule-targeted AAV9-shNUAK1 delivery attenuated ROS/p53 axis-mediated renal tubular senescence, oxidative stress, inflammation, and fibrosis in vitro and in vivo. Mechanistically, chromatin immunoprecipitation (ChIP)-qPCR revealed that transcription factor ETS1 directly binds to the NUAK1 promoter, driving its transcriptional activation in DKD. Furthermore, molecular docking and dynamics simulations identified Asiatic acid (AA) as a potent NUAK1 inhibitor, with a stable binding affinity. AA suppressed NUAK1 expression and downstream pathological processes, ameliorating renal injury in DKD models. These findings elucidate the role and regulatory mechanisms of NUAK1 in modulating ROS/p53 axis-driven tubular senescence and oxidative stress, providing a theoretical basis for structure optimization in drug development targeting NUAK1.</p>