MLKL (mixed lineage kinase domain-like protein) is a pseudokinase that serves as the central executor of necroptosis, a regulated form of inflammatory cell death 1. Despite lacking intrinsic kinase activity, MLKL is activated through phosphorylation by RIPK3 at threonine 357 and serine 358, triggering homotrimerization and translocation to the plasma membrane where it executes programmed necrosis via calcium influx and membrane damage 1. Beyond TNF-induced necroptosis, MLKL mediates nuclear necroptosis following viral infection, where RIPK3-mediated phosphorylation disrupts the nuclear envelope and releases mitochondrial DNA (mtDNA) 2. Released mtDNA activates the cGAS-STING inflammatory pathway, amplifying systemic inflammation 2. Functionally, MLKL's necroptotic activity has context-dependent disease implications: it protects against infections and apoptosis-resistant cancers by triggering antitumor immunity, yet promotes pancreatic cancer metastasis by enhancing immune evasion signals and recruiting macrophage extracellular traps 3. In neurodegenerative diseases, MLKL deficiency reduces neuroinflammation and alleviates motor deficits in Parkinson's disease models and neuronal loss in Alzheimer's disease xenografts 45. MLKL inhibition also ameliorates STING-driven inflammatory diseases including sepsis and inflammatory bowel disease 6. These findings establish MLKL as a therapeutic target for inflammatory and neurodegenerative pathologies.