Necroptosis pathway

The necroptosis pathway is a regulated form of cell death that combines features of both necrosis and apoptosis, characterized by cellular swelling, organelle dysfunction, and plasma membrane rupture (Nature Reviews Molecular Cell Biology, 2017). Unlike apoptosis, necroptosis is caspase-independent and is primarily driven by the activation of receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3) and the downstream effector mixed lineage kinase domain-like protein (MLKL) (Science, 2014). Upon activation, these proteins form a "necrosome" complex where RIPK3 phosphorylates MLKL, leading to its oligomerization and translocation to the plasma membrane, where it causes pore formation and the release of pro-inflammatory damage-associated molecular patterns (DAMPs) (Cell Death & Disease, 2020). This pathway is a significant driver of inflammation and tissue damage in various conditions, including neurodegenerative diseases like Alzheimer's and ALS, as well as ischemia-reperfusion injury and inflammatory bowel disease (Nature Reviews Drug Discovery, 2017). Consequently, the necroptosis pathway has emerged as a promising therapeutic target, with several small-molecule inhibitors of RIPK1 and RIPK3, such as GSK2982772 and Satorexstat, currently in clinical and preclinical development to treat chronic inflammatory and degenerative disorders (ClinicalTrials.gov).

Other names

Programmed necrosisCaspase-independent cell deathRIPK-dependent necrosisNecroptotic cell death

Inhibition of RIPK1 or RIPK3 kinase activity, or prevention of MLKL oligomerization and membrane translocation to block programmed necrotic cell death.