Function mechanism of MLKL [IMAGE: SIMM]

Liver fibrosis affects millions of people worldwide without an effective treatment. In a recent study published in Theranostics, a group of scientists led by Xie Xin from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences (CAS), collaborating with Ding Zhenbin from Zhongshan Hospital, Fudan University, and Gao Zhaobing from CAS’s SIMM, reported the critical function of mixed lineage kinase domain-like protein (MLKL) in liver fibrosis, and suggested that AAV-mediated knockdown of MLKL might provide effective therapy. The journal also published an editorial to comment on this important discovery and discuss future research and application.

Liver fibrosis is a multicellular response to liver injury. Although multiple cell types in the liver contribute to the fibrogenic process, hepatocyte death is considered to be the trigger. It is generally believed that hepatocyte damage causes inflammatory responses, and then the pro-inflammatory cells produce cytokines to activate and transdifferentiate quiescent hepatic stellate cells into myofibroblasts, leading to extracellular matrix deposit and progressive liver fibrosis. Multiple forms of cell death, including necrosis, apoptosis, and necroptosis, have been reported to co-exist in liver diseases. MLKL is the terminal effector in the necroptosis pathway. Although necroptosis has been reported to play an important role in a number of liver diseases, the function of MLKL in liver fibrosis has yet to be unraveled.

In this research the scientists discovered that MLKL level was positively correlated with a number of fibrotic markers in liver samples from both patients with liver fibrosis and animal models. Mlkl deletion in mice significantly reduced clinical symptoms of CCl4- and bile duct ligation (BDL)-induced liver injury and fibrosis.

Further studies indicated that Mlkl-/- blocked liver fibrosis by reducing hepatocyte necroptosis and hepatic stellate cell (HSC) activation. AAV8-mediated specific knockdown of Mlkl in hepatocytes remarkably alleviated CCl4-induced liver fibrosis in both preventative and therapeutic ways.

These results showed that MLKL-mediated signaling played an important role in liver damage and fibrosis, and targeting MLKL might be an effective way to treat liver fibrosis.

For more information, please contact:

Diao Wentong

E-mail: diaowentong@simm.ac.cn

Shanghai Institute of Materia Medica (SIMM),

Chinese Academy of Sciences

Source: Shanghai Institute of Materia Medica (SIMM),

Chinese Academy of Sciences