I-BET151 modulates NLRP3 inflammasome-mediated pyroptosis and exhibits anti-inflammatory activity

Studies have shown that inhibiting the aberrant activation of NOD-like Receptor family pyrin domain containing 3 (NLRP3) inflammasomes can alleviate the onset and progression of various inflammatory diseases. This study investigated the anti-inflammatory mechanism of I-BET151 and its therapeutic effects on colitis and acute lung injury. Through screening of the compound library, it was found that I-BET151 can inhibit NLRP3 inflammasome activation. Enzyme-linked immunosorbent assay (ELISA), high-content screening, immunoprecipitation (IP), Western blot (WB), immunofluorescence etc., were used to study the anti-inflammatory activity and mechanism of action of I-BET151; the therapeutic effects of I-BET151 were assessed in DSS-induced acute colitis and CLP-induced sepsis-associated acute lung injury (SALI) models in mice. The results showed that I-BET151 could inhibit IL-1β secretion and cell Apoptosis. Mechanistically, I-BET151 did not affect mitochondrial damage or Reactive Oxygen Species (ROS) production, but exerted its anti-inflammatory activity by targeting the NLRP3 protein to inhibit NLRP3 inflammasome assembly. In vivo experiments demonstrated that I-BET151 exhibited promising therapeutic effects in both DSS-induced acute colitis and CLP-induced SALI models in mice. In conclusion, I-BET151 is a promising candidate for the treatment of colitis and acute lung injury, primarily exerting its biological activity through the targeting of NLRP3 protein.

Acute lung injury; Inflammatory bowel disease; NLRP3 inflammasome; Pyroptosis; Sepsis.