Mlkl-flox Mouse

Mlkl, short for Mixed lineage kinase domain-like protein, is a pseudokinase and the executioner of necroptosis, a RIPK3-dependent form of regulated necrosis [1,3,6]. Necroptosis is involved in various physiological and pathological processes, and Mlkl plays a crucial role in this programmed cell death pathway. Additionally, Mlkl has been found to have necroptosis-independent functions in processes like receptor internalization, endosomal trafficking, and autophagy [1]. Gene-targeted mouse models are valuable for studying Mlkl's functions.

In gene-knockout mouse models, Mlkl deficiency protected mice from Western diet-induced liver injury by preventing the inhibition of autophagy, indicating that MLKL-dependent, but RIP3-independent, signaling contributes to diet-induced liver injury [2]. In the context of alcohol-associated liver disease, Mlkl deficiency in myeloid cells exacerbated ethanol-mediated bacterial burden, while myeloid MLKL restricted ethanol-induced liver inflammation by regulating macrophage phagocytosis [4]. In a Parkinson's disease mouse model, MLKL deficiency alleviated neuroinflammation and motor deficits [5].

In conclusion, Mlkl has essential functions in necroptosis and other cellular processes. Gene-knockout mouse models have revealed its role in non-alcoholic fatty liver disease, alcohol-associated liver disease, and Parkinson's disease. These studies contribute to understanding Mlkl-related biological mechanisms and provide potential therapeutic targets for these diseases.