Myricetin inhibits NLRP3 inflammasome activation via reduction of ROS-dependent ubiquitination of ASC and promotion of ROS-independent NLRP3 ubiquitination

Highlights: • Myricetin inhibits NLRP3 inflammasome activation. • ROS scavenging activity of myricetin accounts for its inhibition of NLRP3 inflammasome activation. • Ubiquitination of ASC induced by myricetin is attributable to its ROS scavenging activity. • Ubiquitination of NLRP3 is promoted by myricetin and independent of ROS. -- Abstract: Myricetin is a plant-derived flavonoid that exhibits diverse pharmacological properties. The NLRP3 (NLR family, pyrin domain-containing 3 protein) inflammasome is a cytosolic multiprotein complex that plays a critical role in the innate immune response and pathogenesis of multiple inflammatory disorders. The present study found that myricetin inhibited NLRP3 inflammasome assembly via promotion of reactive oxygen species (ROS)-independent ubiquitination of NLRP3 and reduction of ROS-dependent ubiquitination of ASC (apoptosis-associated speck-like protein containing a CARD), which disrupted the interaction between ASC and NLRP3 and inhibited ASC oligomerization. This effect was further confirmed in vivo using mouse models of lipopolysaccharide (LPS)-induced sepsis and alum-induced peritonitis. These results suggest the therapeutic value of myricetin by targeting NLRP3-driven inflammatory diseases.