慢加急性肝衰竭（ACLF）病情危重死亡率高，尚无治愈方法，也无理想动物模型。细菌感染在ACLF病程进展中至关重要。本课题组前期工作中创新构建了一种能完整模拟ACLF患者核心病程的小鼠模型，通过该模型和患者肝组织研究发现ACLF病程中肝再生被抑制，与肝内STAT1过度激活和STAT1/STAT3活性失衡相关。我们推测肝内STAT1/STAT3活性失衡与ACLF发病相关；逆转STAT1/STAT3活性失衡或能阻断病程进展；IL-22激活STAT3发挥肝肾保护及抗感染作用，是逆转STAT1/STAT3活性失衡的最佳选择。本项目首次针对STAT1/STAT3活性失衡与ACLF开展研究，拟通过ACLF小鼠模型、IFNGR敲除小鼠及临床患者，阐明肝内STAT1/STAT3活性失衡在ACLF发病中的作用和机制，明确IL-22能否逆转STAT1/STAT3活性失衡阻断病程进展，为ACLF的治疗提供新策略。

Acute-on-chronic liver failure (ACLF) is a very severe syndrome with rapid progression, poor prognosis and high mortality. There is no curable treatment strategy right now as well as an optimal animal model for the mechanical studies and therapeutic targets screening. Bacterial infection and systemic inflammatory response are crucial in the development of ACLF. A novel ACLF mouse model which could perfectly simulate the clinical course of most ACLF patients has been created in our preliminary work. Liver regeneration is found inhibited in the ACLF mouse model and ACLF patients. The impaired liver regeneration is associated with excessive activation of STAT1 and the unbalance of STAT1/STAT3 activation in the liver. Therefore, we propose that the hepatic unbalance of STAT1/STAT3 activation is associated with the development of ACLF. Overturning the hepatic unbalance of STAT1/STAT3 activation might break off the development of ACLF. Interleukin-22 (IL-22) plays protective roles against liver and kidney injuries as well as anti-bacterial effect via the activation of STAT3. IL-22 is the optimal candidate for overturning the hepatic unbalance of STAT1/STAT3 activation. This proposal focuses on the role and mechanism of hepatic unbalance of STAT1/STAT3 activation for the first time. The novel ACLF model and IFNGR knockout transgenic mice will be applied to clarify the role and mechanism of hepatic unbalance of STAT1/STAT3 in the development of ACLF. Additionally, the animal results will be verified in ACLF patients. Lastly, intervention study will be performed in the novel ACLF model to clarify whether the overturning of hepatic unbalance of STAT1/STAT3 activation could interrupt the progression of ACLF as well as the mechanism. This project may also provide a new immunotherapeutic strategy and basic experimental evidence for ACLF.