Shikonin inhibits NLRP3 inflammasome activation and controls inflammatory disease.

Shikonin (SHK) is a plant-derived naphthoquinone known for its anti-inflammatory activity, though the mechanism remains largely unexplored. The NLRP3 inflammasome, one of the most studied inflammasomes, can cause uncontrolled inflammation and drive various diseases when dysregulated. Here, we confirmed that SHK specifically abolished NLRP3 inflammasome activation by suppressing caspase-1 maturation and the secretion of IL-1β and IL-18. Our data demonstrated that SHK disrupted NLRP3 inflammasome assembly, primarily by blocking NLRP3 and ASC binding, thereby preventing ASC oligomerization and ASC speck formation. Furthermore, SHK reduced reactive oxygen species (ROS) production, inhibiting the generation of oxidized mitochondrial DNA (ox-mtDNA), a known inducer of NLRP3 inflammasome activation. In vivo, we showed that SHK's anti-inflammatory effect in DSS-induced ulcerative colitis (UC) and LPS-induced systemic inflammation associated with the reduction of NLRP3 inflammasome activation, as confirmed by decreased IL-1β and IL-18 release. This paper reveals the mechanism through which SHK inhibits inflammation and provides a potentially effective pharmacological strategy for treating NLRP3-related diseases.