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Updated: Apr 8, 2026
Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
Published on: December 21, 2019
Virtual screening and cellular validation of dolutegravir as a BRD9 inhibitor for attenuating pyroptosis in
Junfang Gai1, Xiaohong Xing2, Chanjuan Gong2
1Department of Pathology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Background:
Peritoneal dialysis is an essential therapy for end-stage renal disease; however, long-term exposure to high-glucose dialysis solutions induces pyroptosis of peritoneal mesothelial cells, promoting peritoneal fibrosis and ultimately leading to technique failure. The involvement of the epigenetic regulator bromodomain-containing protein 9 (BRD9) in this process remains unclear.
Methods:
Structure-based virtual screening of 3,447 FDA-approved drugs from the ZINC database identified dolutegravir as a candidate BRD9 inhibitor. Direct binding and inhibitory activity were validated using cellular thermal shift assays, IC50 determination, and molecular docking. Under high-glucose conditions, the effects of dolutegravir on pyroptosis-related signaling and fibrosis markers in human mesothelial cells were assessed by Western blotting, ELISA, RT-qPCR, and flow cytometry.
Results:
Dolutegravir directly bound to and inhibited BRD9. Under high-glucose stimulation, dolutegravir markedly suppressed NLRP3 inflammasome activation, reduced caspase-1 and gasdermin D cleavage, and decreased interleukin (IL)-1β and IL-18 maturation and release. Mechanistically, BRD9 inhibition accelerated nod-like receptor protein 3 (NLRP3) mRNA degradation and attenuated NLRP3-mediated secretion of the pro-fibrotic factor transforming growth factor-beta 1, leading to downregulation of fibrosis-related markers smooth muscle alpha-actin 2 and collagen type I alpha 1.
Conclusion:
This study identifies dolutegravir as a novel BRD9 inhibitor and demonstrates that BRD9 is a key regulator of high glucose-induced pyroptosis and pro-fibrotic signaling in mesothelial cells via modulation of NLRP3 mRNA stability. These findings suggest a new therapeutic strategy for preventing peritoneal fibrosis and highlight the potential of computational drug repurposing.
