Category: cell_death
Necroptosis is a regulated, caspase-INDEPENDENT lytic cell death — backup death program when apoptosis is blocked (e.g., by viral caspase-8 inhibitors or pharmacological caspase inhibition). The canonical trigger is TNFR1 + caspase-8 inhibition: TNF-α binds TNFR1 → complex I assembly (TRADD + TRAF2/5 + RIPK1 ubiquitinated → NF-κB survival signal). Deubiquitination of RIPK1 (CYLD, A20 regulated) → complex II (RIPK1 + FADD + caspase-8 → apoptosis under normal conditions). When caspase-8 is inhibited or absent → complex IIb (necrosome): RIPK1 + RIPK3 RHIM-domain interaction → amyloid-like filament → RIPK3 autophosphorylation → recruits + phosphorylates MLKL (mixed-lineage kinase-like) at T357/S358 → MLKL trimerization + translocation to plasma membrane → pore formation → osmotic lysis + DAMP release (HMGB1, IL-33, ATP). Differs from pyroptosis (gasdermin-mediated, inflammasome-dependent) and apoptosis (caspase-3/7, no membrane lysis until late). Disease relevance: viral infection (vaccinia caspase-8 inhibitor → triggers necroptosis as antiviral defense; influenza); ischemia-reperfusion (cardiac, brain, kidney); inflammatory bowel disease (intestinal epithelium); psoriasis; ALS; chronic pancreatitis. Therapeutics: necrostatin-1 (RIPK1 inhibitor — preclinical neuroprotection); GSK-872 (RIPK3); GW806742X (MLKL) — all investigational. Several FDA-approved drugs have off-target necroptotic effects: ponatinib (RIPK1/3 + BCR-ABL — CML), dabrafenib (RIPK3 + BRAF — melanoma), sorafenib (multi-kinase + RIPK). Cross-links: [[apoptosis_bcl2_axis]] (parallel programmed death), [[pyroptosis_gasdermin]] (parallel lytic death), [[nfkb_signaling]] (TNFR1 upstream).