GSK2879552 inhibits NLRP3 inflammasome-mediated pyroptosis and acute lung injury through NOX2-ROS signalling axis

Acute lung injury (ALI) is a severe inflammatory disease, and NLRP3 inflammasome plays a crucial role in the initiation and progression of ALI. To date, there are no effective drug treatments for ALI. Thus, it is urgent to develop new therapeutic options to cure ALI. Our study found a new molecule, GSK2879552, which directly suppressed reactive oxygen species (ROS) generation and NLRP3 inflammasome activation, resulting in decreased inflammatory cytokine release and pyroptosis in macrophage. GSK2879552 treatment effectively mitigated the excessive inflammatory response, tissue injury, NLRP3 inflammasome activation, pyroptosis and accumulation of ROS in mouse lung tissue during ALI caused by lipopolysaccharide (LPS) or heat stroke. Meanwhile, GSK2879552 also inhibited the activation of NF-κB pathway and oxidative stress. The molecular docking analysis and in vitro experiments suggested that GSK2879552 suppressed ROS generation may through directly inhibition of NOX2 during NLRP3 inflammasome activation. Taken together, our results suggested that GSK2879552 would be a potential therapeutic option to ALI.