索拉非尼通過(guò)HIF-1α-SLC7A11通路誘導(dǎo)肝星狀細(xì)胞鐵死亡減輕肝纖維化摘要：肝纖維化是肝炎、酒精性肝病和脂肪肝等因素引起的肝臟慢性損傷，致使肝細(xì)胞發(fā)生結(jié)構(gòu)和功能的改變，導(dǎo)致肝內(nèi)纖維化，嚴(yán)重的可導(dǎo)致肝硬化。索拉非尼是一種多靶點(diǎn)抑制劑，對(duì)肝星狀細(xì)胞有很好的抑制作用，但肝細(xì)胞的鐵死亡與其抑制機(jī)制尚未被完全闡明。本文探討了索拉非尼抑制肝星狀細(xì)胞活性的作用機(jī)制，發(fā)現(xiàn)其通過(guò)HIF-1α/SLC7A11通路誘導(dǎo)肝星狀細(xì)胞鐵死亡，從而減輕肝纖維化。結(jié)果表明，索拉非尼可以通過(guò)誘導(dǎo)肝星狀細(xì)胞鐵死亡的方式抑制其增殖能力，減輕肝纖維化病變，為肝病治療提供一種新的治療策略。

關(guān)鍵詞：索拉非尼；肝星狀細(xì)胞；鐵死亡；HIF-1α；SLC7A11；肝纖維化。

Introduction

肝纖維化是肝臟慢性損傷的結(jié)果之一，嚴(yán)重時(shí)可導(dǎo)致肝硬化和肝癌等疾病。而肝星狀細(xì)胞在肝纖維化的發(fā)生和發(fā)展過(guò)程中起著關(guān)鍵性的作用，且對(duì)許多治療藥物都有很好的反應(yīng)。索拉非尼是一種多靶點(diǎn)抑制劑，可以通過(guò)抑制肝星狀細(xì)胞的生長(zhǎng)和分化等方式減輕肝纖維化。然而，肝細(xì)胞鐵死亡與其抑制機(jī)制尚未被完全闡明。

Materialsandmethods

本實(shí)驗(yàn)采用C57BL/6小鼠及原代培養(yǎng)的肝星狀細(xì)胞，研究索拉非尼對(duì)肝星狀細(xì)胞增殖、凋亡和鐵死亡的影響，并探討其與HIF-1α/SLC7A11通路的關(guān)系。

Results

實(shí)驗(yàn)結(jié)果表明，索拉非尼可以通過(guò)抑制肝星狀細(xì)胞的增殖和誘導(dǎo)凋亡等方式對(duì)肝纖維化有很好的治療效果。同時(shí)，索拉非尼還可以誘導(dǎo)肝星狀細(xì)胞的鐵死亡，從而減輕了肝纖維化的病變。此外，本實(shí)驗(yàn)還發(fā)現(xiàn)索拉非尼通過(guò)調(diào)節(jié)HIF-1α/SLC7A11通路來(lái)誘導(dǎo)肝星狀細(xì)胞的鐵死亡，從而發(fā)揮了其治療效果。

Conclusion

本研究表明，索拉非尼可以通過(guò)誘導(dǎo)肝星狀細(xì)胞的鐵死亡來(lái)抑制其增殖能力及肝纖維化的病變，為肝病治療提供了一種新的策略。此外，HIF-1α/SLC7A11通路可能是實(shí)現(xiàn)索拉非尼誘導(dǎo)肝星狀細(xì)胞鐵死亡的機(jī)制之一Liverfibrosisisaseriousdiseasethatcanleadtolivercirrhosisandlivercancer.Hepaticstellatecellsplayakeyroleinthedevelopmentandprogressionofliverfibrosisandhaveagoodresponsetomanytherapeuticdrugs.Sorafenib,amultikinaseinhibitor,canalleviateliverfibrosisbyinhibitingthegrowthanddifferentiationofhepaticstellatecells.However,themechanismbywhichsorafenibinhibitshepaticcellirondeathisnotfullyelucidated.

Inthisstudy,C57BL/6miceandprimaryculturedhepaticstellatecellswereusedtoinvestigatetheeffectofsorafenibontheproliferation,apoptosis,andirondeathofhepaticstellatecells,andtoexploreitsrelationshipwiththeHIF-1α/SLC7A11pathway.

Theresultsshowedthatsorafenibcaneffectivelytreatliverfibrosisbyinhibitingtheproliferationandinducingtheapoptosisofhepaticstellatecells.Moreover,sorafenibcaninduceirondeathofhepaticstellatecells,therebyreducingliverfibrosis.Inaddition,thisstudyalsofoundthatsorafenibinducedtheirondeathofhepaticstellatecellsbyregulatingtheHIF-1α/SLC7A11pathwayandexertingitstherapeuticeffect.

Inconclusion,sorafenibcaninhibittheproliferationandpathologicalchangesofliverfibrosisbyinducingtheirondeathofhepaticstellatecells,providinganewstrategyforthetreatmentofliverdiseases.Inaddition,theHIF-1α/SLC7A11pathwaymaybeoneofthemechanismsbywhichsorafenibinducesirondeathofhepaticstellatecellsFurthermore,thetherapeuticeffectofsorafenibonliverfibrosishasalsobeenlinkedtoitsinhibitionofangiogenesis.StudieshaveshownthatsorafenibcaninhibittheformationofnewbloodvesselsbyblockingtheactionofVEGF,aproteinthatstimulatesthegrowthofbloodvessels.Thisinhibitionofangiogenesiscanleadtoreducedfibrosisandimprovedliverfunction.

Moreover,sorafenibhasbeenshowntoreduceoxidativestressandinflammationinliverfibrosis.Oxidativestressandinflammationarekeydriversofliverfibrosis,andsorafenibhasbeenfoundtoreducetheproductionofreactiveoxygenspeciesandpro-inflammatorycytokines,therebyreducinginflammationandoxidativestressintheliver.

Sorafenibhasalsobeenfoundtohaveanti-tumoreffectsinlivercancer.Aslivercanceroftendevelopsinthesettingoflivercirrhosisandfibrosis,theanti-fibroticeffectsofsorafenibmaycontributetoitsanti-tumoractivity.

Inconclusion,sorafenibisapromisingtreatmentoptionforliverfibrosisandmayhaveadditionalbenefitsinthetreatmentoflivercancer.Itsmechanismofactioninvolvestheinductionofirondeathofhepaticstellatecells,inhibitionofangiogenesis,reductionofoxidativestressandinflammation,andanti-tumoreffects.FurtherstudiesareneededtofullyunderstandthetherapeuticpotentialofsorafenibinliverdiseasesAdditionally,sorafenibhasbeenfoundtohavepotentialtherapeuticbenefitsinotherliverdiseasessuchasportalhypertensionandnon-alcoholicfattyliverdisease(NAFLD).Portalhypertensionisacommoncomplicationoflivercirrhosisandcanleadtofurthercomplicationssuchasesophagealvaricesandascites.Severalstudieshaveshownthatsorafenibcaneffectivelyreduceportalpressurebyregulatingthenitricoxidepathwayandinhibitingintrahepaticangiogenesis.

NAFLDisagrowingconcernworldwideandisassociatedwithobesity,insulinresistance,andmetabolicsyndrome.Itischaracterizedbytheaccumulationoffatintheliver,whichcanprogresstonon-alcoholicsteatohepatitis(NASH)andeventuallycirrhosis.Sorafenibhasbeenshowntoreduceliverinflammation,fibrosis,andoxidativestressinanimalmodelsofNAFLD,suggestingitspotentialasatreatmentoptionforthisdisease.

Despiteitspromisingtherapeuticpotential,sorafenibisnotwithoutsideeffects.Commonsideeffectsincludehand-footsyndrome,diarrhea,fatigue,andweightloss.Insomecases,sorafenibcanalsocausehepatotoxicityandrenalfailure.Therefore,carefulmonitoringandmanagementofpatientsreceivingsorafenibisnecessarytominimizetheriskofadverseeffects.

Inconclusion,sorafenibisapromisingtherapeuticoptionforliverfibrosisandhasadditionalpotentialbenefitsinthetreatmentoflivercancer,portalhypertension,andNAFLD.Itsmechanismofactioninvolvestheinductionofirondeathofhepaticstellatecells,inhibitionofangiogenesis,reductionofoxidativestressandinflammation,andanti-tumoreffects.Furtherstudiesareneeded