Mlkl, short for mixed lineage kinase domain-like protein, is a key effector in necroptosis, a RIPK3-dependent form of regulated necrosis. Necroptosis is involved in various biological processes, and Mlkl's role in this pathway is crucial for understanding programmed cell death [1,4].

In mouse models, Mlkl deficiency protected mice from FFC diet-induced liver injury, suggesting that Mlkl-dependent, but RIP3-independent, signaling contributes to diet-induced liver injury by inhibiting autophagy [2]. In the Gao-binge model of alcohol-associated liver disease, Mlkl deficiency in myeloid cells exacerbated ethanol-mediated bacterial burden and accumulation of immune cells in livers, indicating that myeloid Mlkl restricts ethanol-induced liver inflammation and injury by regulating hepatic immune cell homeostasis and macrophage phagocytosis [3]. Also, in the α-synuclein transgenic mouse model of Parkinson's disease, Mlkl deficiency alleviated neuroinflammation and motor deficits [5].

In conclusion, Mlkl is essential in the necroptosis pathway. Model-based research, especially using Mlkl KO mouse models, has revealed its roles in diseases such as non-alcoholic fatty liver disease, alcohol-associated liver disease, and Parkinson's disease. These findings contribute to understanding the molecular mechanisms of these diseases and may offer potential therapeutic targets related to Mlkl-mediated pathways.

References:

1. Martens, Sofie, Bridelance, Jolien, Roelandt, Ria, Vandenabeele, Peter, Takahashi, Nozomi. 2021. MLKL in cancer: more than a necroptosis regulator. In Cell death and differentiation, 28, 1757-1772. doi:10.1038/s41418-021-00785-0. https://pubmed.ncbi.nlm.nih.gov/33953348/

2. Wu, Xiaoqin, Poulsen, Kyle L, Sanz-Garcia, Carlos, Dasarathy, Srinivasan, Nagy, Laura E. 2020. MLKL-dependent signaling regulates autophagic flux in a murine model of non-alcohol-associated fatty liver and steatohepatitis. In Journal of hepatology, 73, 616-627. doi:10.1016/j.jhep.2020.03.023. https://pubmed.ncbi.nlm.nih.gov/32220583/

3. Wu, Xiaoqin, Fan, Xiude, McMullen, Megan R, Dasarathy, Srinivasan, Nagy, Laura E. 2023. Macrophage-derived MLKL in alcohol-associated liver disease: Regulation of phagocytosis. In Hepatology (Baltimore, Md.), 77, 902-919. doi:10.1002/hep.32612. https://pubmed.ncbi.nlm.nih.gov/35689613/

4. Murphy, James M, Czabotar, Peter E, Hildebrand, Joanne M, Silke, John, Alexander, Warren S. 2013. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. In Immunity, 39, 443-53. doi:10.1016/j.immuni.2013.06.018. https://pubmed.ncbi.nlm.nih.gov/24012422/

5. Geng, Lu, Gao, Wenqing, Saiyin, Hexige, Zhang, Zhuohua, Li, Jixi. 2023. MLKL deficiency alleviates neuroinflammation and motor deficits in the α-synuclein transgenic mouse model of Parkinson's disease. In Molecular neurodegeneration, 18, 94. doi:10.1186/s13024-023-00686-5. https://pubmed.ncbi.nlm.nih.gov/38041169/