Quercetin, a natural flavonoid, protects against hepatic ischemia–reperfusion injury via inhibiting Caspase-8/ASC dependent macrophage pyroptosis

作者：Jiacheng Lin, Fuyang Li, Junzhe Jiao, Yihan Qian, Min Xu, Fang Wang, Xuehua Sun, Tao Zhou, Hailong Wu, Xiaoni Kong · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.05.010 · 被引用次数：52 · 研究领域：Inflammasome and immune disorders、Drug-Induced Hepatotoxicity and Protection、Cell death mechanisms and regulation

INTRODUCTION: Hepatic ischemia-reperfusion injury (IRI) is an inevitable adverse event following liver surgery, leading to liver damage and potential organ failure. Despite advancements, effective interventions for hepatic IRI remain elusive, posing a significant clinical challenge. The innate immune response significantly contributes to the pathogenesis of hepatic IRI by promoting an inflammatory cytotoxic cycle. We have reported that blocking GSDMD-induced pyroptosis in innate immunity cells protected hepatic IRI from inflammatory injury. However, the search for effective pyroptosis inhibitors continues. OBJECTIVES: This study aims to evaluate whether quercetin, a natural flavonoid, can inhibit GSDMD-induced pyroptosis and mitigate hepatic IRI. METHODS: We established the hepatic IRI murine model and cellular pyroptosis model to evaluate the efficacy of quercetin. RESULTS: Quercetin effectively alleviated hepatic IRI-induced tissue necrosis and inflammation. We found that during hepatic IRI, the cleavage of GSDMD occurred in hepatic macrophages, but not in other non-parenchymal cells. Quercetin inhibited the cleavage of GSDMD in macrophages. Moreover, we found that quercetin blocked the ASC assembly to inhibit the formation of NLRP3 inflammasomes and AIM2 inflammasomes, suppressing macrophage pyroptosis. Co-immunoprecipitation experiments confirmed that quercetin inhibited the interaction between ASC and Caspase-8, which is the mechanism of ASC complex and inflammasome form...