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

Jiacheng Lin; Fuyang Li; Junzhe Jiao; Yihan Qian; Min Xu; Fang Wang; Xuehua Sun; Tao Zhou; Hailong Wu; Xiaoni Kong

doi:10.1016/j.jare.2024.05.010

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

J Adv Res. 2024 May 10:S2090-1232(24)00200-5. doi: 10.1016/j.jare.2024.05.010. Online ahead of print.

Authors

Jiacheng Lin¹, Fuyang Li¹, Junzhe Jiao¹, Yihan Qian¹, Min Xu¹, Fang Wang¹, Xuehua Sun¹, Tao Zhou², Hailong Wu³, Xiaoni Kong⁴

Affiliations

¹ Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: emperorztxy@126.com.
³ Shanghai Key Laboratory of Molecular Imaging, Collaborative Innovation Center for Biomedicines, Shanghai University of Medicine and Health Sciences, Shanghai, China. Electronic address: wuhl@sumhs.edu.cn.
⁴ Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: xiaonikong@shutcm.edu.cn.

PMID: 38735388
DOI: 10.1016/j.jare.2024.05.010

Abstract

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 formation. Overexpression of Caspase-8 abolished the anti-pyroptosis effect of quercetin in NLRP3 and AIM2 inflammasome signaling. Furthermore, we found that the hepatoprotective activity of quercetin was reduced in myelocytic GSDMD-deficient mice.

Conclusion: Our findings suggest that quercetin has beneficial effects on hepatic IRI. Quercetin could attenuate hepatic IRI and target inhibition of macrophage pyroptosis via blocking Caspase-8/ASC interaction. We recommend that quercetin might serve as a targeted approach for the prevention and personalized treatment of hepatic IRI in perioperative patients.

Keywords: Alternative therapy; Dietary supplement; Hepatic ischemia reperfusion; Macrophage; Pyroptosis; Quercetin.