OpinionTargetingFerroptosis:NewHopeforAs-Yet-IncurableDiseasesMarcusConrad,1,2,*SvenjaM.Lorenz,1andBettinaProneth1Attainingcontroloverlifeanddeathdecisionsfacilitatestheidentificationofnewtherapeuticstrategiesfordiseasesaffectedbyearlycelllossorresistancetocelldeath.Inthiscontext,ferroptosis,aprevailingformofnon-apoptoticcelldeathmarkedbytheiron-dependentoxidativedestructionoflipidbilayersandmeta-bolicaberrations,hasattractedoverwhelminginterestamongbasicresearchersandcliniciansduetoitsrelevanceforanumberofdegenerativediseases,suchasneurodegeneration,ischemia/reperfusioninjury(IRI),andorganfailure,aswellastherapy-resistanttumors.Astheferroptoticdeathpathwayoffersvariousdruggablenodes,itisanticipatedthatthepreclinicalandclinicaldevelopmentofferroptosismodulatorswillunleashunprecedentedopportunitiesforthetreat-mentofas-yet-incurablediseases.MolecularPrinciplesofFerroptosisThetraditionalperceptionthatcelldeathcanbeclassifiedonlyasapoptosis,thearchetypalformofprogrammedcelldeath,ornecrosis(seeGlossary),whichwaslongconsideredtobeunreg-ulatedwithnoprospectsforpharmacologicalintervention,isnowbeingchallengedbythenotionthatnecroticcelldeathcanalsoproceedinaregulatedfashion,asfirstdescribedfornecroptosis[1].Morethanadozenformsofregulatednecrosishavebeendescribed,althoughitremainsuncertainwhetherallofthem:(i)aretrulyindependent;(ii)overlap;or(iii)areconstrainedtocertaincelltypes[2].Nonetheless,amongtheseformsofregulatednecrosis,ferroptosishassparkedtremendousinterestasitemergestobetherootcauseofanumberofdegenerativediseasesandmayprovideanAchillesheelforbarelytreatabletumors[3].Ferroptosiswasfirstdescribedasanon-apoptoticformofcelldeathmarkedbyimpairedcystine(i.e.,theoxidizedformofcysteine)uptakeintocells,glutathione(GSH)depletionandiron-dependentlipidperoxidation[4].However,longbeforethetermferroptosiswascoined,multipleseeminglydisparatelinesofevidence,obtainedbytheexplorationofvariousbiochemical,cellular,andmetabolicprocessesincludingcysteine/seleniumavailability,GSHbiosy...
