Artemisinin-derived artemisitene blocks ROS-mediated NLRP3 inflammasome and alleviates ulcerative colitis.

Artemisinins are well-known antimalarial drugs with clinical safety. In addition to antimalarial effects, their anti-inflammatory and immunoregulatory properties have recently attracted much attention in the treatment of inflammatory diseases. However, these artemisinins only have sub-millimolar anti-inflammatory activity in vitro, which may pose a high risk of toxicity in vivo with high doses of artemisinins. Here, we identified another derivative, artemisitene, which can increase the activity of inhibiting the NLRP3 pathway by more than 200-fold through introducing a covalent binding group while retaining the peroxide bridge structure. Mechanistically, artemisitene inhibits the production of ROS (especially mtROS) and prevents the assembly and activation of NLRP3 inflammasome, thereby inhibiting IL-1β production. In addition, it can also block IL-1β secretion mediated by NLRC4 and AIM2 inflammasome and IL-6 production. Furthermore, treatment with artemisitene significantly attenuated inflammatory response in DSS-induced ulcerative colitis. Our work provides a potential artemisinin derivative, which is worthy of further structural optimization based on pharmacokinetic properties as a drug candidate for inflammatory disorders.