Mixed lineage kinase domain-like protein (MLKL) is a pseudokinase that belongs to the protein kinase superfamily and contains a protein kinase-like domain but lacks catalytic activity. It plays a crucial role in necroptosis, a form of regulated cell death. When activated by receptor-interacting protein kinase 3 (RIPK3), MLKL oligomerizes and translocates to the plasma membrane, causing membrane permeabilization and ultimately leading to cell death. Besides its canonical role in necroptosis, MLKL has been found to be associated with various cellular organelles, such as the mitochondrion, lysosome, endosome, endoplasmic reticulum, and nucleus, where it may regulate diverse pathophysiological events. Additionally, MLKL has necroptosis-independent functions in processes like receptor internalization, ligand-receptor degradation, endosomal trafficking, autophagy, and nuclear functions. Its involvement in multiple diseases and potential as a therapeutic target are also being actively investigated.
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