Brazilin is a natural product inhibitor of the NLRP3 inflammasome

Excessive or aberrant NLRP3 inflammasome activation has been implicated in the progression and initiation of many inflammatory conditions; however, currently no NLRP3 inflammasome inhibitors have been approved for therapeutic use in the clinic. Here we have identified that the natural product brazilin effectively inhibits both priming and activation of the NLRP3 inflammasome in cultured murine macrophages, a human iPSC microglial cell line and in a mouse model of acute peritoneal inflammation. Through computational modeling, we predict that brazilin can adopt a favorable binding pose within a site of the NLRP3 protein which is essential for its conformational activation. Our results not only encourage further evaluation of brazilin as a therapeutic agent for NLRP3-related inflammatory diseases, but also introduce this small-molecule as a promising scaffold structure for the development of derivative NLRP3 inhibitor compounds. [Display omitted] •The natural-product brazilin inhibits NLRP3 inflammasome priming and activation•Brazilin enhances NRF2 signaling, which may contribute to inhibition of priming•Computational modeling demonstrates favorable docking of brazilin with NLRP3•Effect shown in murine macrophages, human microglia and peritoneal inflammation model Biological sciences; Biochemistry; Biomolecules; Natural product biochemistry