The NLRP3 inflammasome plays a crucial role in innate immune-mediated inflammation and contributes to the pathogenesis of multiple autoinflammatory, metabolic and neurodegenerative diseases, but medications targeting the NLRP3 inflammasome are not available for clinical use. RRx-001 is a well-tolerated anticancer agent currently being investigated in phase III clinical trials, but its effects on inflammatory diseases are not known. Here, we show that RRx-001 is a highly selective and potent NLRP3 inhibitor that has strong beneficial effects on NLRP3-driven inflammatory diseases. RRx-001 inhibits the activation of the canonical, noncanonical, and alternative NLRP3 inflammasomes but not the AIM2, NLRC4 or Pyrin inflammasomes. Mechanistically, RRx-001 covalently binds to cysteine 409 of NLRP3 via its bromoacetyl group and therefore blocks the NLRP3-NEK7 interaction, which is critical for the assembly and activation of the NLRP3 inflammasome. More importantly, RRx-001 treatment attenuates the symptoms of lipopolysaccharide (LPS)-induced systemic inflammation, dextran sulfate sodium (DSS)-induced colitis and experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our study identifies RRx-001 as a new potential therapeutic agent for NLRP3-driven diseases.
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We thank Dr. Feng Shao (National Institute of Biological Sciences, Beijing, China) for providing the TcdB toxin. This research was supported by the National Key Research and Development Program of China (grant numbers 2019YFA0508503 and 2020YFA0509101), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant number XDB29030102), the National Natural Science Foundation of China (grant numbers 82003765, 81821001, 31770991, and 91742202), the Fundamental Research Funds for the Central Universities and the University Synergy Innovation Program of Anhui Province (GXXT-2019-026), the Natural Science Foundation of Anhui Province (1908085QC99) .
R.Z., W.J. and Y.C. are named as inventors on China National Intellectual Property Administration Application Serial No. 202011472140.0 related to RRx-001.
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Chen, Y., He, H., Lin, B. et al. RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor. Cell Mol Immunol 18, 1425–1436 (2021). https://doi.org/10.1038/s41423-021-00683-y
- NLRP3 inflammasome
- inflammatory diseases