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

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

  • Int Immunopharmacol. 2026 Mar 15:173:116305. doi: 10.1016/j.intimp.2026.116305.
Menghao Zeng 1,  Wei Xing 2,  Guibin Liang 1,  Fangfang Yuan 2,  Wenhua Wang 2,  Jie Liu 2,  Zhihui He 3
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; Sepsis Translational Medicine Key Laboratory of Hunan Province, Central South University, Changsha, Hunan 410078, China.
  • 2 Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
  • 3 Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; Sepsis Translational Medicine Key Laboratory of Hunan Province, Central South University, Changsha, Hunan 410078, China. Electronic address: [email protected].
PMID: 41628514 DOI: 10.1016/j.intimp.2026.116305
Abstract

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.

Keywords

NLRP3 inflammasome; Sepsis; α-Methylene-γ-butyrolactone 3.

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