The NLRP3 inflammasome is dysregulated in autoinflammatory disorders caused by inherited mutations and contributes to the pathogenesis of several chronic inflammatory diseases. In this study, we discovered that disulfiram, a safe US Food and Drug Administration (FDA)-approved drug, specifically inhibits the NLRP3 inflammasome but not the NLRC4 or AIM2 inflammasomes. Disulfiram suppresses caspase-1 activation, ASC speck formation, and pyroptosis induced by several stimuli that activate NLRP3. Mechanistically, NLRP3 is palmitoylated at cysteine 126, a modification required for its localization to the trans-Golgi network and inflammasome activation, which was inhibited by disulfiram. Administration of disulfiram to animals inhibited the NLRP3, but not NLRC4, inflammasome in vivo. Our study uncovers a mechanism by which disulfiram targets NLRP3 and provides a rationale for using a safe FDA-approved drug for the treatment of NLRP3-associated inflammatory diseases.
Keywords: CP: Immunology; NLRP3; disulfiram; gasdermin D; inflammasome; palmitoylation.
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