Arteannuin B, a novel NLRP3 inhibitor, suppresses NLRP3 inflammasome in macrophages and alleviates NLRP3-related diseases.

The NLRP3 inflammasome plays pivotal roles in inflammatory pathogenesis, yet developing specific inhibitors remains challenging due to toxicity risks and incomplete mechanistic targeting. FDA has authorized no NLRP3 inhibitor for therapeutic application in clinical use. Here, we characterize Arteannuin B (ArtB), a sesquiterpene lactone from Artemisia annua, as a novel NLRP3 inhibitor via screening assay. ArtB was shown to selectively disrupt NLRP3 inflammasome assembly by binding to NLRP3, thereby blocking ASC oligomerization. We demonstrated that ArtB dose-dependently inhibited secretion of Caspase-1 and IL-1β, and suppressed NLRP3-mediated pyroptosis in both murine and human macrophages. Molecular dynamics assay and molecular docking revealed that ArtB stabilizes a structural rearrangement within NACHT domain, directly binds to Gly271 and Ser331, sterically hindering NLRP3-NEK7 interaction. In murine ulcerative colitis and acute lung injury models, ArtB attenuated inflammation and tissue pathology in an NLRP3-dependent manner. Moreover, the therapeutic efficacy of ArtB was abolished by the elimination of Nlrp3 in mouse model. These findings establish ArtB as a drug candidate for NLRP3-driven pathologies, with translational advantages rooted in its natural product lineage and potential repurposing utility for inflammasome-related disorders.