Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity

Hongbin He(University of Science and Technology of China), Hua Jiang(University of Science and Technology of China), Yun Chen(Xiamen University), Jin Ye(University of Science and Technology of China), Aoli Wang(Chinese Academy of Sciences), Chao Wang(University of Science and Technology of China), Qingsong Liu(Chinese Academy of Sciences), Gaolin Liang(University of Science and Technology of China), Xianming Deng(Xiamen University), Wei Jiang(University of Science and Technology of China), Rongbin Zhou(University of Science and Technology of China)
Nature Communications
June 25, 2018
10.1038/s41467-018-04947-6
Cited by 777Open Access
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Abstract

Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT domain to block the interaction between NLRP3 and NEK7, thereby inhibiting NLRP3 inflammasome assembly and activation. Importantly, Ori has both preventive or therapeutic effects on mouse models of peritonitis, gouty arthritis and type 2 diabetes, via inhibition of NLRP3 activation. Our results thus identify NLRP3 as the direct target of Ori for mediating Ori's anti-inflammatory activity. Ori could serve as a lead for developing new therapeutics against NLRP3-driven diseases.

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