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内质网应激通路在纳米ZnO诱导小鼠肝毒性中的作用及机制.docx

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内质网应激通路在纳米ZnO诱导小鼠肝毒性中的作用及机制 Title:RoleandMechanismofEndoplasmicReticulumStressPathwayinNano-ZnOInducedHepatotoxicityinMice Abstract: Nano-ZnO(zincoxide)isawidelyusednanoparticlewithvariousapplications,includingpersonalcareproducts,foodadditives,andpharmaceuticals.However,thepotentialhepatotoxicityofnano-ZnOhasraisedconcernsregardingitssafety.Recently,increasingevidencesuggeststhatendoplasmicreticulum(ER)stressplaysacriticalroleinthedevelopmentofhepatotoxicityinducedbyvariousnanoparticles.Inthisreview,wefocusontheroleandmechanismoftheERstresspathwayinnano-ZnOinducedhepatotoxicityinmiceanddiscusspotentialtherapeuticstrategiesformanagingnano-ZnO-inducedliverinjury. Introduction: ZnOnanoparticleshaveuniquephysicochemicalpropertiesthatmakethemsuitableforvariousapplications;however,theirtoxiceffectsontheliverhavebeenwidelyreported.Theliveristheprimarysitefornanoparticlemetabolismandclearance,makingitsusceptibletodamagefromnano-ZnOexposure.ERstresshasemergedasacriticaleventinnanoparticle-inducedhepatotoxicity,andunderstandingtheunderlyingmechanismscouldleadtothedevelopmentofeffectivepreventiveandtherapeuticstrategies. EndoplasmicReticulumStressPathway: TheERisanessentialorganelleresponsibleforproteinfolding,lipidsynthesis,andcalciumhomeostasis.DisruptionofERhomeostasistriggerstheunfoldedproteinresponse(UPR),aprotectivemechanismtorestoreERfunction.However,prolongedorsevereERstressleadstocelldysfunctionandapoptosis.TheUPRismediatedbythreeprimarysignalingpathways:inositol-requiringprotein1α(IRE1α),proteinkinaseRNA-likeERkinase(PERK),andactivatingtranscriptionfactor6(ATF6).ThesepathwaysactinconcerttoalleviatetheERstressandrestorecellularhomeostasis. MechanismsofZnONanoparticles-inducedERStress: Severalmechanismshavebeenproposedtoexplainhownano-ZnOinducesERstressinhepatocytes.Firstly,thedirectinteractionbetweennano-ZnOandERmembraneproteinsdisruptscalciumhomeostasis,leadingtoERstress.Secondly,nano-ZnOgeneratesreactiveoxygenspecies(ROS)withinhepatocytes,whichinducesoxidativestres