Necroptosis is a programmed form of cell death triggered by death receptor ligands and stimuli able to induce expres-sion of death receptor ligands. In particular conditions, programmed cell death resembles necrosis and relies on a unique molecular pathway primed under apoptotic defi-cient conditions. The hub of the necroptosis pathway is the receptor-interacting protein kinase 1 (RIPK1), which recruits RIPK3 and mixed lineage kinase domain-like protein (MLKL) to form a regulatory necrosome complex. In vitro and in vivo studies provide evidence that RIPK1 and its partners are critical pathogenic determinants and markers of progres-sion and severity in several different inflammatory disorders, including neurodegenerative diseases, such as amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer???s disease, Parkinson???s disease, multiple sclerosis and Hunting-ton???s disease. A growing body of evidence pinpoints RIPK1 and the necrosome as novel potential therapeutic targets able to inhibit multiple cell death pathways and amelio-rate neuroinflammation alone or in combination with other treatments.
