β-sitosterol alleviated HFD-induced atherosclerosis by regulating the MAPK/Nrf2/NLRP3 pathway in ApoE−/− mice

Abstract

Background Atherosclerosis (AS), driven by chronic inflammation and oxidative stress, remains a leading cause of cardiovascular morbidity. While β-sitosterol, a dietary phytosterol, shows therapeutic potential for AS, its mechanisms remain unclear. This study aimed to explore whether β-sitosterol alleviates AS by modulating the MAPK/Nrf2/NLRP3 pathway. Methods ApoE−/− mice fed a high-fat diet (HFD) were treated with β-sitosterol for 8 weeks. Lipid profiles, aortic plaque area, oxidative stress markers, and inflammatory mediators were analyzed. Nrf2 pathway activity and NLRP3 inflammasome components were assessed using ELISA, qRT-PCR, and histochemical assays. Results β-sitosterol significantly reduced serum total cholesterol, LDL-C, and aortic plaque area in HFD-fed mice. It suppressed the MAPK pathway and NLRP3 inflammasome activation while downregulating MMP-2/9 expression. Additionally, β-sitosterol activated the Nrf2 pathway, increasing catalase protein (CAT) activity and reducing oxidative stress in liver tissue. However, it showed limited effects on NF-κB, IL-6, IL-10, and certain antioxidants. Conclusion β-sitosterol ameliorates AS by attenuating lipid accumulation, inflammation, and oxidative stress via coordinated regulation of the MAPK/Nrf2/NLRP3 pathways. These findings highlight its potential as a therapeutic agent, though clinical studies are warranted to confirm efficacy and safety in humans.