CellDeath&Differentiationhttps://doi.org/10.1038/s41418-018-0173-9REVIEWARTICLEFerroptosisandnecroinflammation,ayetpoorlyexploredlinkBettinaProneth1●MarcusConrad1Received:19April2018/Revised:14June2018/Accepted:10July2018©ADMCAssociazioneDifferenziamentoeMorteCellulare2018AbstractFerroptosisisanon-apoptoticformofcelldeathcharacterizedbyoverwhelmingiron-dependentlipidperoxidation,whichcontributestoanumberofpathologies,mostnotablytissueischemia/reperfusioninjury,neurodegenerationandcancer.Cysteineavailability,glutathionebiosynthesis,polyunsaturatedfattyacidmetabolismandmodulationofthephospholipidomearethekeyeventsofthisnecroticcelldeathpathway.Non-enzymaticandenzymaticlipoxygenase(LOX)-mediatedlipidperoxidationoflipidbilayersisefficientlycounteractedbytheglutathione(GSH)/glutathioneperoxidase4(GPX4)axis.Preliminarystudiessuggestthatburstingferroptoticcellsreleasepro-inflammatorydamage-associatedmolecularpatterns(DAMPs)thattriggertheinnateimmunesystemasexemplifiedbydiseasedkidneyandbraintissueswhereferroptosiscontributestoorgandemiseinapredominantmanner.TheGSH/GPX4nodeisknowntocontroltheactivitiesofLOXandprostaglandin-endoperoxidesynthase(PTGS)viatheso-calledperoxidetone.SinceLOXandPTGSproductsdohavepro-andanti-inflammatoryeffects,onemayspeculatethattheseenzymescontributetotheferroptoticprocessonseverallevelsincell-autonomousandnon-autonomousways.Hence,thisreviewprovidesthereaderwithanoutlineonwhatiscurrentlyknownaboutthelinkbetweenferroptosisandnecroinflammationanddiscussescriticaleventsthatmayalerttheinnateimmunesysteminearlyphaseswhencellsbecomesensitizedtowardsferroptosis.Facts●Ferroptosisisaregulatedformofnecroticcelldeathcharacterizedbyiron-dependentlipidperoxidation.●GPX4isthekeyregulatorofferroptosisbyquenchinglipidperoxidation.●Initialdatasuggestthatferroptoticcellstriggertheinnateimmunesysteminmousemodelsofbrainandkidneydisease.●Theglutathione(GSH)/GPX4nodecontrolsLOXandPTGSactivitiesviatheso-calledperoxidetone.OpenquestionsWhatisthenatureofDAMPsrele...
