Lin Jiacheng, Li Fuyang, Jiao Junzhe, Qian Yihan, Xu Min, Wang Fang, Sun Xuehua, Zhou Tao, Wu Hailong, Kong Xiaoni
Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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.
J Adv Res. 2025 Apr;70:555-569. doi: 10.1016/j.jare.2024.05.010. Epub 2024 May 10.
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.
This study aims to evaluate whether quercetin, a natural flavonoid, can inhibit GSDMD-induced pyroptosis and mitigate hepatic IRI.
We established the hepatic IRI murine model and cellular pyroptosis model to evaluate the efficacy of quercetin.
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.
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.
肝缺血再灌注损伤（IRI）是肝脏手术后不可避免的不良事件，会导致肝损伤和潜在的器官衰竭。尽管取得了进展，但针对肝IRI的有效干预措施仍然难以捉摸，这构成了重大的临床挑战。先天性免疫反应通过促进炎症细胞毒性循环，在肝IRI的发病机制中起重要作用。我们曾报道，阻断先天性免疫细胞中GSDMD诱导的细胞焦亡可保护肝IRI免受炎症损伤。然而，对有效细胞焦亡抑制剂的探索仍在继续。
本研究旨在评估天然黄酮类化合物槲皮素是否能抑制GSDMD诱导的细胞焦亡并减轻肝IRI。
我们建立了肝IRI小鼠模型和细胞焦亡模型，以评估槲皮素的疗效。
槲皮素有效减轻了肝IRI诱导的组织坏死和炎症。我们发现，在肝IRI期间，GSDMD的切割发生在肝巨噬细胞中，而在其他非实质细胞中未发生。槲皮素抑制了巨噬细胞中GSDMD的切割。此外，我们发现槲皮素阻断ASC组装以抑制NLRP3炎性小体和AIM2炎性小体的形成，从而抑制巨噬细胞焦亡。免疫共沉淀实验证实，槲皮素抑制了ASC与Caspase-8之间的相互作用，这是ASC复合物和炎性小体形成的机制。Caspase-8的过表达消除了槲皮素在NLRP3和AIM2炎性小体信号通路中的抗细胞焦亡作用。此外，我们发现槲皮素在骨髓细胞GSDMD缺陷小鼠中的肝保护活性降低。
我们的研究结果表明，槲皮素对肝IRI具有有益作用。槲皮素可通过阻断Caspase-8/ASC相互作用减轻肝IRI并靶向抑制巨噬细胞焦亡。我们建议，槲皮素可能作为围手术期患者肝IRI预防和个性化治疗的靶向方法。
