Harnessing FDA-approved dipyridamole to inhibit NLRP3 inflammasome and improve outcomes of acute lung injury in sepsis

Aberrant activation of the NLRP3 inflammasome is critically involved in sepsis-induced acute lung injury (ALI), with inhibition of this pathway emerging as a promising therapeutic approach. This study identifies Dipyridamole, an FDA-approved drug, as a novel inhibitor of the NLRP3 inflammasome. Mechanistically, Dipyridamole suppresses mitochondrial ROS release and directly interacts with NEK7, thereby preventing its association with NLRP3 and impeding inflammasome complex assembly. In an LPS-induced sepsis model, Dipyridamole significantly ameliorated ALI, reduced inflammatory responses, and improved survival rates in model mice. Additionally, Dipyridamole effectively inhibited NLRP3 inflammasome activation in lung tissue. These findings position Dipyridamole as a potent NLRP3 inflammasome inhibitor with substantial therapeutic potential for managing sepsis-induced ALI.