肝衰竭病程进展快，病死率高，发病机制仍不明。最新研究报道，程序性坏死是一种可调控的细胞坏死，在多种炎症损伤相关的疾病中发挥重要作用。本课题组前期发现程序性坏死关键调控分子MLKL等在肝衰竭患者血清及小鼠肝组织中表达上调，抑制MLKL上游的激酶活性具肝脏保护效应，提示MLKL可能通过介导肝细胞程序性坏死参与肝衰竭病程进展。本项目拟采用肝衰竭小鼠，研究程序性坏死信号通路关键分子在肝衰竭病程中的作用，探讨其与炎症损伤、氧应激、凋亡等的内在联系；过表达/低表达MLKL，观察其表达水平对小鼠肝衰竭病程的影响并探讨机制；利用细胞体外诱导程序性坏死，针对线粒体损伤环节，阐明肝衰竭中MLKL介导肝细胞程序性坏死的调控机制；同时，建立前瞻性肝衰竭临床队列，明确程序性坏死及关键调控分子MLKL与肝衰竭发生及预后转归的关系，为深入理解肝衰竭发病机制提供新证据，也为降低肝衰竭死亡率提供新的干预靶点和治疗策略。

Liver failure is still a major health problem with aggressive progression and poor prognosis. The underlining pathogenesis of liver failure remains unclear. Recently, necroptosis, a novel demonstrated programmed cell death has been implicated in mediating multiple inflammation associated diseases. Our preliminary studies found that the expression of the key regulator of necroptosis, MLKL and its upstream molecules were up-regulated in the serum of liver failure patients and liver tissue of liver failure mice. Blocking the kinase activity of RIPK1, an up-stream regulator of MLKL in the necroptosis pathway, by necrostatins could inhibit the activation of necroptosis and ameliorate liver injury in the presence of LPS/D-GalN. The results suggested the involvement of necroptosis in the progression of liver failure. Therefore, we proposed to utilize murine liver failure model to further investigate the role of key regulators of the necroptosis pathway in the progression of liver failure and its relationship with hepatic inflammation, oxidative stress and apoptosis, and to further determine whether MLKL plays a vital role in the progression of liver failure and its relative mechanism by using MLKL over-expressed or knock-down murine model. Furthermore, in ex-vivo experiment, focusing on the mitochondrial, we proposed to isolate primary hepatocytes of mice to investigate the regulatory mechanism of MLKL in mediating hepatocyte necroptosis. Meanwhile, liver failure patient cohort would be prospectively established to validate the impact of necroptosis in liver failure patients and to determine its prognostic value. The study will provide new evidences for a deeper understanding of the pathophysiology mechanisms of liver failure and would also provide new therapeutic strategies to lower the high mortality of liver failure.