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

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

  • Eur J Pharm Sci. 2025 Sep 27:214:107296. doi: 10.1016/j.ejps.2025.107296.
Hung-Jin Huang 1,  Yen-Chung Lin 2,  Li-Ju Ho 3,  Ruei-Yu Su 4,  Wen-Chih Liu 5,  Hui-Wen Chiu 6
Affiliations

Affiliations

  • 1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 2 Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan.
  • 3 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
  • 4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pathology, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan; Department of Pathology and Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan.
  • 5 Section of Nephrology, Department of Medicine, Antai Medical Care Corporation Antai Tian-Sheng Memorial Hospital, Pingtung, Taiwan; Department of Biology and Anatomy, National Defense Medical University, Taipei, Taiwan; Department of Nursing, Meiho University, Pingtung, Taiwan. Electronic address: wayneliu55@gmail.com.
  • 6 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan; Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; PhD. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: leu3@tmu.edu.tw.
PMID: 41022315 DOI: 10.1016/j.ejps.2025.107296
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.

Keywords

Chronic kidney disease; MD simulation; QSAR; SIRT2; Virtual screening.

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