Activationofthep62-Keap1-NRF2PathwayProtectsAgainstFerroptosisinHepatocellularCarcinomaCellsXiaofangSun,1ZhanhuiOu,1RuochanChen,2XiaohuaNiu,1DeChen,1RuiKang,2andDaolinTang1,2Ferroptosisisarecentlyrecognizedformofregulatedcelldeathcausedbyaniron-dependentaccumulationoflipidreactiveoxygenspecies.However,themolecularmecha-nismsregulatingferroptosisremainobscure.Here,wereportthatnuclearfactorerythroid2-relatedfactor2(NRF2)playsacentralroleinprotectinghepatocellularcarcinoma(HCC)cellsagainstferroptosis.Uponexposuretoferroptosis-inducingcompounds(e.g.,erastin,sorafenib,andbuthioninesulfoximine),p62expressionpreventedNRF2degrada-tionandenhancedsubsequentNRF2nuclearaccumulationthroughinactivationofKelch-likeECH-associatedprotein1.Additionally,nuclearNRF2interactedwithtranscriptionalcoactivatorsmallv-mafavianmusculoaponeuroticfibrosarcomaoncogenehomologpro-teinssuchasMafGandthenactivatedtranscriptionofquinoneoxidoreductase-1,hemeoxygenase-1,andferritinheavychain-1.Knockdownofp62,quinoneoxidoreductase-1,hemeoxygenase-1,andferritinheavychain-1byRNAinterferenceinHCCcellspromotedferroptosisinresponsetoerastinandsorafenib.Furthermore,geneticorpharmacologicinhibitionofNRF2expression/activityinHCCcellsincreasedtheanticanceractivityoferastinandsorafenibinvitroandintumorxenograftmodels.Conclusion:Thesefindingsdemonstratenovelmolecularmechanismsandsignalingpathwaysofferroptosis;thestatusofNRF2isakeyfactorthatdeterminesthetherapeuticresponsetoferroptosis-targetedtherapiesinHCCcells.(HEPATOLOGY2016;63:173-184)Hepatocellularcarcinoma(HCC)inmenisthesecondleadingcauseofcancer-relateddeathworldwide.1TreatmentoptionsforadvancedHCC,includingsurgicalresectionandnonsurgicaltherapies,areoflimitedeffectiveness.Sorafenib,amulti-plekinaseinhibitor,isthefirstsystemictherapytoimprovesurvivalinHCCandisnowastandardtreat-mentpendingapprovalbytheUSFoodandDrugAdministrationforpatientswithunresectableHCC.2,3However,sorafenibhasbeenshowntoprovidelimitedsurvivalbenefits,suggestingtheexistenceofprimaryanda...
