Dimethyl fumarate covalently modifies Cys673 of NLRP3 to exert anti-inflammatory effects

Summary: The NLRP3 inflammasome plays a pivotal role in various chronic inflammation-driven human diseases. However, no drugs specifically targeting NLRP3 inflammasome have been approved by the Food and Drug Administration (FDA) of the United States. In our current study, we showed that dimethyl fumarate (DMF) efficiently suppressed the activation of the NLRP3 inflammasome induced by multiple agonists and covalently modified Cys673 of NLRP3, thereby impeding the interaction between NLRP3 and NEK7. The inhibitory effect of DMF was nullified by anaplerosis of the Cys673 mutant (but not the wild-type) NLRP3 in Nlrp3−/− THP-1 cells. In vivo experiments, DMF demonstrated protective effects in the dextran sodium sulfate (DSS)-induced ulcerative colitis of WT mice, but not in Nlrp3−/− mice. In summary, our study identified DMF as a direct covalent inhibitor of NLRP3 and a potential candidate for the treatment of NLRP3 inflammasome-mediated diseases.