Virtual screening and cellular validation of dolutegravir as a BRD9 inhibitor for attenuating pyroptosis in peritoneal mesothelial cells
- Ren Fail. 2026 Dec;48(1):2644768. doi: 10.1080/0886022X.2026.2644768.
- 1. Department of Pathology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
- 2. Department of Nephrology, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
- 3. Department of Nephrology, Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
- 4. Department of Nephrology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 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.