Mixed Lineage Kinase Domain‐Like Protein (MLKL): From Mechanisms to Therapeutic Opportunities

Abstract Lytic forms of regulated cell death (RCD) rely on the activation and recruitment of executioner proteins. The mixed lineage kinase domain‐like protein (MLKL) acts as the executioner in the necroptosis pathway, transitioning from an inactive to active state through phosphorylation, oligomerization, membrane recruitment, and membrane insertion, ultimately forming membrane hotpots. These mechanisms involve protein–protein interactions between receptor‐interacting protein kinase 3 (RIPK3) and MLKL, MLKL phosphorylation, protein–protein interactions between MLKL and MLKL, and MLKL‐lipid interactions. In this review, the specificity of MLKL activation mechanisms is discussed across different species and describe the processes by which MLKL transitions from an auto‐inhibited to a membrane‐embedded state. The opportunities are further explored for targeting MLKL, including small molecule inhibitors and functionally interacting proteins.