Britannin as a novel NLRP3 inhibitor, suppresses inflammasome activation in macrophages and alleviates NLRP3-related diseases in mice

Jing-jing Shao1,2, Wei-feng Li2, Jin-feng Sun3,4, Zai-shou Zhuang5, Ju-lian Min1, Xiao-hong Long2, Gao-jun Wu1, Hao-wen Xu2,3, Guang Liang1,3
1 Department of Cardiology and Medical Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
3 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 311399, China
4 Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, School of Pharmaceutical Sciences, Yanbian University, Yanji 133002, China
5 Affiliated Cangnan Hospital, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
Correspondence to: Hao-wen Xu:, Guang Liang:,
DOI: 10.1038/s41401-023-01212-5
Received: 4 September 2023
Accepted: 6 December 2023
Advance online: 3 January 2024


Overactivation of the NLRP3 inflammasomes induces production of pro-inflammatory cytokines and drives pathological processes. Pharmacological inhibition of NLRP3 is an explicit strategy for the treatment of inflammatory diseases. Thus far no drug specifically targeting NLRP3 has been approved by the FDA for clinical use. This study was aimed to discover novel NLRP3 inhibitors that could suppress NLRP3-mediated pyroptosis. We screened 95 natural products from our in-house library for their inhibitory activity on IL-1β secretion in LPS + ATP-challenged BMDMs, found that Britannin exerted the most potent inhibitory effect with an IC50 value of 3.630 µM. We showed that Britannin (1, 5, 10 µM) dose-dependently inhibited secretion of the cleaved Caspase-1 (p20) and the mature IL-1β, and suppressed NLRP3-mediated pyroptosis in both murine and human macrophages. We demonstrated that Britannin specifically inhibited the activation step of NLRP3 inflammasome in BMDMs via interrupting the assembly step, especially the interaction between NLRP3 and NEK7. We revealed that Britannin directly bound to NLRP3 NACHT domain at Arg335 and Gly271. Moreover, Britannin suppressed NLRP3 activation in an ATPase-independent way, suggesting it as a lead compound for design and development of novel NLRP3 inhibitors. In mouse models of MSU-induced gouty arthritis and LPS-induced acute lung injury (ALI), administration of Britannin (20 mg/kg, i.p.) significantly alleviated NLRP3-mediated inflammation; the therapeutic effects of Britannin were dismissed by NLRP3 knockout. In conclusion, Britannin is an effective natural NLRP3 inhibitor and a potential lead compound for the development of drugs targeting NLRP3.

Keywords: inflammation; NLRP3 inflammasome; Britannin; gouty arthritis; acute lung injury; systemic infection

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