Formanyyears,researchershavedividedcelldeathpro-cessesintothosethatareregulatedandthosethatareaccidental.Thefirst-discoveredformofregulatedcelldeath,apoptosis,wasusedasasynonymforregulatedcelldeathandevenforprogrammedcelldeathinthecon-textofdevelopmentandhomeostasis,whereasthetermnecrosiswasreservedasasynonymforaccidentalcelldeath.Thisparadigmwasimbuedwiththenotionthatonlyapoptosiswasconsideredtherapeuticallytractable,astheaccidentalandunregulatednatureofitsnecroticcounterpartmeantthatitwasdeemedundruggable.Thisperspectiveledtothesystematicneglectofthepossibilitythatnon-apoptoticcelldeathsubroutinescouldrepresentcausativeprocessesindiseaseandasourceofpotentiallypharmacologicallytractabledrugtargets.Thislong-standingparadigminthefieldofcelldeathhasrecentlybeenchallengedandoverturnedbytherecognitionthattumournecrosisfactor(TNF)caninduceregulatedcelldeathwithapoptoticornecroticfeaturesinacontext-dependentmanner1.Owingtoitsregulatednature,thisnecroticformofcelldeathwastermednecroptosis.Sofar,necroptosisisthebest-studiedformofregulatednon-apoptoticcelldeathandhashelpedtoilluminatetwobasicprinciples.First,regulated,and,indeed,developmentallypro-grammed,celldeathisnotrestrictedtoapoptosis,andsecond,celldeathpathwayscanbeinterconnected.Thesefactorsneedtobetakenintoconsiderationwhenpharmacologicalstrategiesforcytoprotectiveinterventionareconceivedanddeployed.Theestablishmentofnecroptosisasanalternativeformofregulatedcelldeathhasresultedinseveralstud-iesimplicatingnecroptosisasthemaincontributortocelldeathindiverseconditions.However,becauseotherregulatedformsofnon-apoptoticcelldeathresultinginnecroticmorphology(cytoplasmicswellingandlossofplasmamembraneintegrity)areinterconnectedandinterdependent,acarefulandcriticalre-evaluationofthesestudiesisrequiredtounequivocallydeter-minewhichprogrammesareactuallyelicitedunderspecificconditions2.Necroptosisandotherregulatednon-apoptoticformsofcelldeath,suchasferroptosis,parthanatosandcyclophilinD-(CypD)-dependentnecrosis,haveattracted...
