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

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-28 DOI:10.1016/j.intimp.2025.114543

Zheyi Wu , Niwen Huang , Chao Li , Muzhi Lin , Zhangrong Chen , Wei Li , Haiyan Zhou

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引用次数: 0

Abstract

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.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.