ReviewFerroptosis:DeathbyLipidPeroxidationWanSeokYang1,4,*andBrentR.Stockwell1,2,3,*Ferroptosisisaregulatedformofcelldeathdrivenbylossofactivityofthelipidrepairenzymeglutathioneperoxidase4(GPX4)andsubsequentaccumulationoflipid-basedreactiveoxygenspecies(ROS),particularlylipidhydroperoxides.Thisformofiron-dependentcelldeathisgenetically,biochemically,andmor-phologicallydistinctfromothercelldeathmodalities,includingapoptosis,unregulatednecrosis,andnecroptosis.Ferroptosisisregulatedbyspecificpathwaysandisinvolvedindiversebiologicalcontexts.Herewesummarizethediscoveryofferroptosis,themechanismofferroptosisregulation,anditsincreasinglyappreciatedrelevancetobothnormalandpathologicalphysiology.DiscoveryofFerroptosisCelldeathisessentialforfundamentalphysiologicalprocessessuchasdevelopment,immunity,andtissuehomeostasis;moreover,celldeathisoftendysregulatedindegenerativeandneoplasticdiseases.Bothapoptoticandnonapoptoticcelldeathmodalitieshaveincreasinglybeennecessarytoexplaindiversebiologicalprocessesinvolvingcellloss.Tworegulatedformsofnonapoptoticcelldeath,necroptosisandferroptosis,havebeenshownrecentlytoplaysignificantrolesinnumerousbiologicalcontexts[1,2].Whilethemechanismsandphysiologicalrelevanceofnecroptosishavebeenreviewedrecently[3],wefocushereonthemolecularmechanismscontrollingferroptosisanditsrelevancetohealthanddisease.EarlylifeonEarthdevelopedintheabsenceofoxygen[4];approximately2.4billionyearsago,thecompositionoftheatmospherechangeddramatically,probablyduetooxygenproductionfromemergingphotosyntheticorganisms[5,6].AfterthisGreatOxygenationEvent,oxygenintheatmosphereultimatelyrosefromonlytraceabundancestoitscurrent21%abundance[5,6].Theemergenceofcopiousamountsofoxygenintheatmospherewaschallengingfororganismswithmembraneshavingpolyunsaturatedlipidsthatcontainbis-allyliccarbons,becausethesearehighlysusceptibletolipidperoxidationinthepresenceofoxygen[7].Thisperoxidationreactionisdramaticallyacceleratedbydivalentmetals,especiallyFe(II)[7].Whilelifeprobablyoriginate...
