β-Sitosterol suppresses NLRP3 Inflammasome activation and Pyroptosis in myocardial ischemia/reperfusion injury via inhibition of PPARγ2.

Background: β-Sitosterol, a plant-derived sterol, has demonstrated potential therapeutic effects in cardiovascular diseases, particularly myocardial ischemia-reperfusion injury (MIRI). Our study investigates its underlying mechanism through regulation of pyroptosis.

Methods: To understand the role of β-sitosterol in protecting cardiomyocytes, MIRI rats were treated with β-sitosterol. Rats' cardiac functions were monitored, and hearts were harvested for histology and Western Blot analysis. Immunofluorescence, immunoblot, enzyme-linked immunosorbent assay, as well as overexpression and knockdown techniques were utilized in this study to investigate the molecular mechanisms underlying the cardioprotective effects of β-sitosterol.

Results: Our results showed that β-Sitosterol significantly reduced H/R-induced pyroptosis in cardiomyocytes by decreasing cleaved caspase-1, gasdermin D (GSDMD), interleukin-1β (IL-1β), and interleukin-18 (IL-18). Immunofluorescence staining confirmed suppression of NLRP3 inflammasome activation. Notably, β-Sitosterol inhibited pyroptosis induced by ATP and ATP/LPS through the regulation of PPARγ2. Moreover, PPARγ2 upregulation promoted ATP and ATP/LPS-induced pyroptosis through the NLRP3/caspase-1/GSDMD pathway. In vivo, β-sitosterol alleviates myocardial ischemia-reperfusion injury-induced cardiac dysfunction and myocardial fibrosis in rats.

Conclusions: These findings provide new evidence supporting β-sitosterol as a potential therapeutic agent for cardiovascular diseases involving ischemic injury. Its protective effects may be mediated through targeting PPARγ2 and modulating NLRP3-dependent pyroptosis.