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

TLDR

Oridonin, a major component of the traditional Chinese herb Rabdosia rubescens, exhibits anti‑inflammatory activity but its target was previously unknown, while NLRP3 is a central inflammasome component implicated in many chronic inflammatory diseases. The authors propose Ori as a lead compound for developing therapeutics against NLRP3‑driven diseases. Ori covalently binds cysteine 279 in the NACHT domain of NLRP3, blocking its interaction with NEK7 and thereby preventing inflammasome assembly and activation. Ori specifically and covalently inhibits NLRP3 inflammasome, reducing inflammation in mouse models of peritonitis, gouty arthritis, and type 2 diabetes, confirming NLRP3 as its direct target.

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.