Mlkl, or mixed lineage kinase domain-like protein, is a pseudokinase and a key downstream effector of receptor interacting protein kinase 3 (RIP3) in the necroptotic pathway of programmed cell death [1,2,3,4,5,7]. Necroptosis is a RIPK3-dependent form of regulated necrosis, and Mlkl serves as the executioner of this process [1,7]. Additionally, Mlkl has been implicated in various non-necroptotic functions such as receptor internalization, endosomal trafficking, autophagy, and inflammasome regulation [1,7].

Mlkl deficiency in mice has provided insights into its role in different disease conditions. In a murine model of non-alcohol-associated fatty liver and steatohepatitis, Mlkl-dependent but RIP3-independent signaling contributed to diet-induced liver injury by inhibiting autophagy [2]. In alcohol-associated liver disease, myeloid Mlkl restricts ethanol-induced liver inflammation and injury by regulating hepatic immune cell homeostasis and macrophage phagocytosis [5]. In the α-synuclein transgenic mouse model of Parkinson's disease, Mlkl deficiency alleviated neuroinflammation and motor deficits [6].

In conclusion, Mlkl is essential in the necroptotic pathway and also has diverse non-necroptotic functions. Gene knockout mouse models have revealed its significance in diseases such as non-alcoholic fatty liver disease, alcohol-associated liver disease, and Parkinson's disease, highlighting its potential as a therapeutic target in these disease areas.