α-Methylene-γ-butyrolactone 3 inhibits the activation of NLRP3 inflammasome in sepsis by blocking both the priming and inflammasome assembly.

Excessive NLRP3 inflammasome activation is implicated in pathologies like sepsis. While the histone acetyltransferase inhibitor α-methylene-γ-butyrolactone 3 (MB-3) is typically studied in cancer and epigenetic research, its anti-inflammatory potential remains largely unexplored. This study investigated the effect of MB-3 on NLRP3 inflammasome activation in both cellular and animal models. Results demonstrated that MB-3 treatment significantly downregulated NLRP3-associated inflammatory cytokines and proteins in vitro and in vivo. Mechanistic studies revealed that MB-3 acts by dual inhibition of the NLRP3 inflammasome. It disrupted the critical protein interactions between NLRP3-ASC and NLRP3-NEK7 and reduced ASC and NLRP3 oligomerization, thereby blocking the inflammasome assembly. Furthermore, MB-3 exhibited a protective effect on mitochondrial integrity by rescuing the loss of mitochondrial membrane potential and reducing the production of reactive oxygen species (ROS). In conclusion, these findings identify MB-3 as an effective inhibitor of the NLRP3 inflammasome, operating by blocking both the priming and assembly stages of activation. The results suggests that MB-3 is a promising potential therapeutic candidate for the treatment of NLRP3-driven inflammatory diseases.