脓毒症是由于宿主对感染的免疫反应失调，而导致多器官功能障碍的严重疾病。其是目前ICU病人死亡的主要原因之一。脓毒症常可引起肝损伤甚至肝衰竭，且肝脏损伤程度与不良预后直接相关。由脓毒症引起的肝损伤已引起高度重视，但目前机制不明。我们的预实验结果表明LPS可通过诱导N-GSDMD释放，导致肝细胞焦亡。同时，LPS-caspase4/11-GSDMD级联相关基因在肝细胞高表达。质谱分析显示KLHL22与GSDMD共沉淀，KLHL22-CUL3-RBX1泛素化酶E3的亚基亦高表达于肝细胞。因此我们推测：在脓毒症发生过程中，LPS-caspase4/11-GSDMD级联释放N-GSDMD致肝细胞焦亡。本实验将从动物、细胞及分子水平，分析KLHL22-CUL3-RBX1泛素化GSDMD致其降解从而抑制肝损伤。本研究旨在揭示GSDMD泛素化修饰及其在脓毒症性肝损伤中保护机制，为脓毒症治疗提供新靶点。

Sepsis is a serious disease with multiple organ dysfunction due to host immune response to infection. It is one of the main causes of death in ICU patients. Sepsis can often lead to liver injury and even liver failure, and the degree of liver injury is directly related to adverse prognosis. Liver injury caused by sepsis has attracted much attention, but the mechanism is unknown. Our preliminary experiment indicated that LPS induced the pyroptosis of hepatocyte due to cleavage of GSDMD to release N-GSDMD. The genes associated with LPS-caspase4/11-GSDMD cascade were highly expressed in liver tissues and hepatocytes. Mass spectrum assay identified the co-immunoprecipitation of KLHL22 with GSDMD. The subunits of KLHL22-CUL3-RBX1 ubiquitin ligase E3 were also highly expressed in hepatocytes. Therefore, we speculate that during sepsis, LPS-caspase4/11-GSDMD cascade release of N-GSDMD leads to hepatic pyogenic death. In this study, we analyzed the degradation of KLHL22-CUL3-RBX1 ubiquitin GSDMD to inhibit liver injury at animal, cell and molecular levels. The aim of this study was to reveal the GSDMD ubiquitin modification and its protective mechanism in sepsis-induced liver injury, and to provide a new target for the treatment of sepsis.