A rapid administration of GW4064 inhibits the NLRP3 inflammasome activation independent of farnesoid X receptor agonism.

GW4064 is a small molecule known to be an agonist of the nuclear farnesoid X receptor (FXR). We found that GW4064 inhibits the NLR family CARD domain containing 3 (NLRP3) inflammasome activation in an FXR-independent manner as evidenced by its similar inhibitory effect on NLRP3 inflammasome activation in FXR-deficient macrophages. Interestingly, GW4064 decreases the nigericin-induced oligomerization and ubiquitination of ASC which is critical for the NLRP3 inflammasome activation. In vivo results indicate that GW4064 could partially rescue the symptoms of NLRP3-dependent inflammatory disease models. These results not only necessitate cautious interpretation of the biological function of GW4064 as an FXR agonist, but also provide a potential therapeutic approach using GW4064 in the treatment of NLRP3-related diseases.