Repurposing of FDA-approved drugs by targeting SIRT2 to alleviate inflammatory response and kidney injury.

Abstract

Chronic kidney disease (CKD) involves the gradual loss of kidney function, usually caused by inflammation and fibrosis. The Sirtuin 2 (SIRT2) is predominantly expressed in proximal epithelial tubular cells, and specific inhibition of SIRT2 activity has been shown to alleviate fibrotic kidneys. We focus on targeting SIRT2 to discover a potent FDA-approved drug as a nephroprotective treatment for patients with CKD. Candidate compounds with high affinity and inhibitory effect for SIRT2 protein were filtered using structure-based virtual screening and quantitative structure-activity relationships (QSARs) prediction mode. The suggested candidate with favorable docking scores and predicted inhibitory activity was further examined for structural stability in 100 ns MD simulations. In addition, trajectories from dynamic simulation revealed that gliquidone remains bound to the target protein's active site in dynamic conditions. Gliquidone exhibited strong binding affinity among the screened drugs toward SIRT2 and maintained stable interactions with key residues in MD trajectories. Experimental validation was performed using a hydrogen peroxide-induced HK-2 cell injury model, followed by western blot analysis of autophagy, NLRP3 inflammasome, and fibrosis-related proteins. The experimental data also confirmed that gliquidone significantly improved HK-2 cell viability under oxidative stress, upregulated autophagy-related proteins (Beclin 1, p62 and LC3-II), suppressed NLRP3 inflammasome activation, and reduced fibrosis-associated factors (collagen type I, CTGF and PAI-1). These findings demonstrate that gliquidone exerts nephroprotective effects by modulating autophagy, inflammation, and fibrotic pathways. Overall, this study provides mechanistic insights supporting gliquidone as a promising repurposed candidate as a possible therapeutic drug for preventing CKD.