Tranilast directly targets NLRP3 to treat inflammasome‐driven diseases

The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases, but the medications targeting NLRP3 inflammasome are not available in clinic. Here, we show that tranilast (TR), an old anti‐allergic clinical drug, is a direct NLRP3 inhibitor. TR inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanismly, TR directly binds to the NACHT domain of NLRP3 and suppresses the assembly of NLRP3 inflammasome by blocking NLRP3 oligomerization. In vivo experiments show that TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3 inflammasome‐related human diseases, including gouty arthritis, cryopyrin‐associated autoinflammatory syndromes, and type 2 diabetes. Furthermore, TR is active ex vivo for synovial fluid mononuclear cells from patients with gout. Thus, our study identifies the old drug TR as a direct NLRP3 inhibitor and provides a potentially practical pharmacological approach for treating NLRP3‐driven diseases. Synopsis Tranilast (TR), an anti‐allergic clinical drug, is here reported as a NLRP3 inflammasome inhibitor with beneficial effects for NLRP3‐driven diseases. By direct binding to NLRP3, it inhibits its oligomerization and subsequent inflammasome assembly, caspase‐1 activation and IL‐1β production. TR specifically inhibits NLRP3 inflammasome activation in both human and mouse cells. TR binds to NLRP3 and inhibits its oligomerization and inflammasome complex formation. TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3‐driven diseases. Graphical Abstract Tranilast (TR), an anti‐allergic clinical drug, is here reported as a NLRP3 inflammasome inhibitor with beneficial effects for NLRP3‐driven diseases. By direct binding to NLRP3, it inhibits its oligomerization and subsequent inflammasome assembly, caspase‐1 activation and IL‐1β production.