Resibufogenin protects against atherosclerosis in ApoEmice through blocking NLRP3 inflammasome assembly.

Abstract

INTRODUCTION: Atherosclerosis (AS), a major cause of cardiovascular diseases, is characterized by lipid accumulation and chronic inflammation within arterial walls. Traditional treatments, such as statins, are often ineffective for many patients, highlighting the need for novel therapeutic strategies. OBJECTIVE: This study explores the potential of Resibufogenin (RBG) as an NLRP3 inflammasome inhibitor for treating AS in ApoEmice. METHODS: We performed experiments encompassing cellular studies, animal model assessments, molecular simulations, and binding assays to assess RBG's impact on the NLRP3 inflammasome, inflammatory cytokine release, and foam cell formation. RESULTS: RBG treatment alleviated AS in ApoEmice, evidenced by reduced body weight, smaller atherosclerotic plaques, and improved serum lipid profiles. Transcriptomics and molecular biology demonstrated that RBG suppressed the expression of key inflammatory markers such as NLRP3. RBG also reduced macrophage infiltration and promoted polarization toward the anti-inflammatory M2 phenotype. Molecular docking, SPR, Pull-down studies identified a non-covalent interaction between RBG and the CYS-279 residue of NLRP3, confirming its role as a potent NLRP3 inhibitor. CONCLUSION: RBG effectively inhibits NLRP3 inflammasome activation, reduces pro-inflammatory cytokine release, and decreases formation of foamy macrophages, thereby slowing the progression of AS. Although these findings highlight RBG as a promising therapeutic approach for cardiovascular diseases, further research is necessary to assess its safety and effectiveness in humans and to investigate possible synergistic effects with other treatments.