0 引言

常見的肝臟疾病包括病毒性肝炎、酒精性肝病(alcoholic liver disease,ALD)、非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)以及相關(guān)的肝纖維化、肝硬化和肝細(xì)胞癌(hepatocellular carcinoma,HCC)等.由于肝臟疾病的病理機(jī)制復(fù)雜,其發(fā)生與發(fā)展是多因素、多步驟的復(fù)雜過程,藥物及手術(shù)治療存在一定的局限性,肝移植是終末期肝病唯一有效的治療方法,但肝源的缺乏和終身用藥的副作用限制了其應(yīng)用.因此,積極探索肝臟疾病的病理機(jī)制及藥物治療方法具有重要意義.已有證據(jù)表明cGAS-STING信號通路參與多種肝臟疾病的病理過程,它觸發(fā)了與自噬、免疫逃逸和有絲分裂相關(guān)的炎癥風(fēng)暴,同時在宿主抵抗病毒和細(xì)菌入侵過程也起到至關(guān)重要的作用,是目前肝臟疾病機(jī)制及治療研究的一個重要潛在方向.

1 cGAS-STING信號通路概述

STING(stimulator of interferon genes,STING),也稱干擾素激活基因,首次在2008年被揭示是先天性免疫信號的調(diào)節(jié)劑.cGAS-STING信號通路是天然免疫領(lǐng)域的重大發(fā)現(xiàn).當(dāng)存在病毒或其他致病因素所導(dǎo)致的細(xì)胞DNA損傷時,損傷的DNA會誘導(dǎo)環(huán)狀GMP-AMP合成酶(cyclic GMP-AMP synthase,cGAS)構(gòu)象變化,并催化環(huán)鳥嘌呤腺嘌呤(cyclic GMP-AMP,cGAMP)的產(chǎn)生.cGAMP作為第二信使,招募位于內(nèi)質(zhì)網(wǎng)上的效應(yīng)器蛋白STING,促進(jìn)STING從內(nèi)質(zhì)網(wǎng)通過高爾基體到核周圍的運輸,STING作為通路的關(guān)鍵效應(yīng)蛋白,會促使TANK結(jié)合激酶1(TANK-bingding kinase 1,TBK1)磷酸化激活,隨后一方面促進(jìn)干擾素調(diào)節(jié)因子3(interferon regulatory factor 3,IRF3)核轉(zhuǎn)位,產(chǎn)生Ⅰ型干擾素(interferons,IFNs);另一方面,STING會活化IκB激酶(inhibitor of nuclear factor kappa-B kinase,IKK),IKK將細(xì)胞內(nèi)NF-κB-IκB復(fù)合物的IκB亞基調(diào)節(jié)位點的絲氨酸磷酸化,進(jìn)而被蛋白酶降解,從而釋放NF-κB二聚體進(jìn)入細(xì)胞核,與有NF-κB結(jié)合位點的基因結(jié)合,啟動轉(zhuǎn)錄進(jìn)程,促進(jìn)炎性因子分泌,發(fā)揮促進(jìn)炎癥的作用

.由于STING在多種細(xì)胞類型中廣泛表達(dá),并能調(diào)控不同的程序性細(xì)胞死亡途徑,所以對cGASSTING信號通路的認(rèn)識在過去十年中迅速增長,許多研究表明cGAS-STING信號通路參與多種疾病,包括炎癥、感染、自身免疫性疾病、代謝紊亂和腫瘤等

.最近的研究表明

,cGAS-STING信號通路也參與了病毒性肝炎、ALD、NAFLD、肝損傷和HCC等多種疾病的病理過程,我們總結(jié)了cGAS-STING信號通路在多種肝臟疾病中的作用及其潛在治療意義,深入了解cGAS-STING信號通路可能為治療肝臟疾病提供新的思路.

2 cGAS-STING信號通路與肝臟疾病

2.1 cGAS-STING信號通路與慢性肝炎 病毒性肝炎是一個重大的公共衛(wèi)生問題,從流行趨勢來看,乙型肝炎病毒(hepatitis B virus,HBV)與丙型肝炎病毒(hepatitis C virus,HCV)仍是慢性肝炎、肝硬化和HCC最重要的致病因素

.因此,探討HBV感染的細(xì)胞內(nèi)分子機(jī)制至關(guān)重要.有研究報道顯示cGAS-STING信號通路有著優(yōu)越的抗病毒能力,可檢測細(xì)胞質(zhì)中的病毒DNA,如單純皰疹病毒-1、人類免疫缺陷病毒、腺病毒、人類巨細(xì)胞病毒等

.當(dāng)然,除了識別DNA病毒,它也可以識別并抵抗RNA病毒,特別是陽性的單鏈RNA(single stranded RNA,ssRNA)病毒

.在對HBV的研究過程中,有研究者發(fā)現(xiàn)cGAS-STING信號通路通過激活下游Toll樣受體3(toll-like receptor 3,TLR3)產(chǎn)生干擾素β(interferon β,IFN-β)抑制HBV的復(fù)制

.另一方面,HBV可逃避cGAS效應(yīng)通路及免疫系統(tǒng)的識別和攻擊,導(dǎo)致肝細(xì)胞慢性感染,例如HBV聚合酶可破壞STING的K63泛素化,并通過與STING相互作用最終抑制IFN-Ⅰ的產(chǎn)生

.Hu等

將HBV病毒質(zhì)粒(pHBv1.3)與表達(dá)cGAS和STING質(zhì)粒共轉(zhuǎn)染至HepG2細(xì)胞,發(fā)現(xiàn)當(dāng)HepG2細(xì)胞被共轉(zhuǎn)染后,乙肝病毒RNA水平顯著降低,而HBV DNA水平和e抗原分泌減少5倍,乙肝病毒RNA在細(xì)胞中比例明顯減少,并且在人肝細(xì)胞系L02和pHBV1.3轉(zhuǎn)染的小鼠模型中也獲得了類似的結(jié)果.相比于肝細(xì)胞,Kupffer細(xì)胞(kupffer cells,KCs),即肝巨噬細(xì)胞有更高的STING蛋白表達(dá)量,它可以吞噬病毒感染細(xì)胞,減輕機(jī)體病毒攜帶量,但同時,HBV病毒核心也可以通過cGAS-STING信號通路激活Kupffer細(xì)胞上的Toll樣受體2(toll-like receptor 2,TLR2),并通過產(chǎn)生白介素10(interleukin 10,IL-10)抑制HBV特異性T細(xì)胞應(yīng)答

.肝細(xì)胞中cGAS-STING表達(dá)水平的降低以及針對cGAS-STING信號轉(zhuǎn)導(dǎo)的HBV逃逸機(jī)制在一定程度上促進(jìn)了肝細(xì)胞慢性HBV感染.在HCV與STING相關(guān)的研究中.有報道稱HCV編碼的非結(jié)構(gòu)蛋白4B(non-structuralprotein4B,NS4B)能夠直接與STING結(jié)合削弱了STING和TBK1之間的相互作用,阻斷干擾素信號的轉(zhuǎn)導(dǎo)

.另有研究顯示在機(jī)體受到外來刺激時,內(nèi)質(zhì)網(wǎng)局部的STING可以移位到細(xì)胞質(zhì)并與TBK1結(jié)合,這時NS4B蛋白可能在內(nèi)質(zhì)網(wǎng)保留STING,從而抑制STING與TBK1的相互作用

.NS4B還可能通過競爭性地與STING結(jié)合干擾線粒體抗病毒信號蛋白(mitochondrial antiviral signaling protein,MAVS),阻斷STING和MAVS之間的相互作用,強(qiáng)烈抑制MAVS介導(dǎo)的IRF-3的磷酸化.綜上所述,cGAS-STING信號通路與HBV及HCV之間有著密切關(guān)聯(lián),靶向cGAS-STING信號通路可能是增強(qiáng)宿主對HBV及HCV免疫應(yīng)答的一種治療選擇.

1.2.2 觀察指標(biāo) 所有患者分別在基線及治療12個月，禁食12 h后清晨空腹抽取靜脈血5 mL，2 h內(nèi)以3 500轉(zhuǎn)速分離血清，于本院檢驗科行生化全套及PSA等檢查，檢測總?cè)８视?TG)、總膽固醇(TC)、

想要避免一味比較的習(xí)慣，真正有效的辦法不是禁止做某事，而是用做另一件事來替代。如果我們要減少有害的比較，就得讓自己去做有益的比較。

2.2 cGAS-STING信號通路與酒精性肝病 ALD造成肝硬化的死亡率占肝硬化相關(guān)疾病的50%,ALD的病因和發(fā)病機(jī)制復(fù)雜,目前先天免疫功能障礙和過度炎癥反應(yīng)已被證實是ALD發(fā)生的重要原因之一

,對ALD患者肝細(xì)胞的基因分析結(jié)果顯示,cGAS-STING通路的激活水平與ALD的嚴(yán)重程度相關(guān).cGAS可通過連接蛋白(主要是Cx32)組成的細(xì)胞間通道驅(qū)動肝細(xì)胞和非實質(zhì)細(xì)胞中IRF3的激活

,IRF3的激活可引起酒精誘導(dǎo)的肝細(xì)胞細(xì)胞凋亡,繼而促進(jìn)炎癥反應(yīng),導(dǎo)致ALD的發(fā)生.因此,cGAS和Cx32是ALD發(fā)病機(jī)制的關(guān)鍵,可作為潛在的ALD治療靶點.

2.4 cGAS-STING信號通路與肝癌 病毒性肝炎,如HBV、HCV是HCC發(fā)生的重要原因,此外還有過度飲酒、脂肪肝等.目前,現(xiàn)代醫(yī)學(xué)治療肝癌方式主要包括手術(shù)切除、射頻消融術(shù)、肝動脈栓塞化療術(shù)及放化療等,但臨床療效有限,預(yù)后較差,嚴(yán)重影響了患者的生存質(zhì)量

.近年來,發(fā)現(xiàn)cGAS-STING在抗腫瘤免疫反應(yīng)中起著積極的作用,其與HCC的發(fā)生發(fā)展也密切相關(guān).有報道顯示,在一定的條件下,癌細(xì)胞的細(xì)胞核和線粒體DNA會以多種形式泄漏到胞質(zhì)中,cGAS-STING信號通路被激活,促進(jìn)IFN-Ⅰ的釋放,IFN-Ⅰ的產(chǎn)生增強(qiáng)了宿主抵抗腫瘤細(xì)胞的能力.同時,IFN-Ⅰ對樹突狀細(xì)胞(dendritic cells,DCs)的成熟至關(guān)重要

,DCs中cGASSTING信號可以通過吞噬死亡或受損的癌細(xì)胞、外泌體轉(zhuǎn)移和cGAMP連接被激活,然后,DCs在IFN-Ⅰ的誘導(dǎo)下遷移到腫瘤組織,激活腫瘤特異性CD8+T細(xì)胞,從而誘導(dǎo)全身抗腫瘤免疫來控制局部和遠(yuǎn)處的腫瘤生長

.此外,癌細(xì)胞中cGAS-STING信號通路的激活也會招募免疫細(xì)胞清除癌細(xì)胞,例如增強(qiáng)癌細(xì)胞對自然殺傷細(xì)胞(natural killer cells,NKs)和細(xì)胞毒性T淋巴細(xì)胞(cytotoxic T lymphocyte,CTL)的免疫攻擊的敏感性

.同時,基于對多個數(shù)據(jù)庫的分析,確定了cGAS-STING通路的關(guān)鍵基因與人類樣本的HCC表型之間的聯(lián)系,發(fā)現(xiàn)絲氨酸-蘇氨酸激酶PI3家族成員ATR和ATM是HCC中潛在的激酶靶點,ATR抑制劑增強(qiáng)了肝癌放療的抗腫瘤活性,并且可激活胞質(zhì)中cGAS-STING通路

.

2.3 cGAS-STING信號通路與非酒精性脂肪性肝病NAFLD已成為全球最主要的慢性肝病之一

,是當(dāng)下研究的熱點,但同時,其預(yù)防和治療也存在諸多難點,目前尚無批準(zhǔn)上市的特異性藥物

.NAFLD常發(fā)生于肥胖人群和代謝綜合征患者,主要以肝細(xì)胞內(nèi)脂肪過度沉積為主要特征,病程包括單純性脂肪肝、非酒精性脂肪性肝炎和NASH相關(guān)肝硬化

.有研究表明,在高脂肪飲食(high fatty diet,HFD)的小鼠模型中,STING參與了糖脂代謝過程,喂養(yǎng)高果糖而不表達(dá)STING的小鼠表現(xiàn)出肝臟脂肪、炎癥及纖維化的減少,這表明STING的激活可能促進(jìn)了肝臟脂肪及炎癥的生成

.此外,STINGIRF3軸參與了NAFLD和早期ALD中凋亡通路的激活,STING-IRF3軸可通過與線粒體上相關(guān)蛋白Bcl-2、Bax相互作用,激活線粒體凋亡通路,造成肝細(xì)胞凋亡,上調(diào)炎癥通路

.另有研究發(fā)現(xiàn)單核細(xì)胞源性巨噬細(xì)胞和肝臟KCs中STING的激活促進(jìn)了TBK1、c-Jun氨基末端激酶(c-Jun-N-terminal kinase,JNK)和NF-kB的磷酸化

,導(dǎo)致轉(zhuǎn)化生長因子α(transforming growth factor-α,TGF-α)和白介素1β(interleukin-1β,IL-1β)生成,這些細(xì)胞因子的產(chǎn)生觸發(fā)肝細(xì)胞炎癥通路,并產(chǎn)生轉(zhuǎn)化生長因子β1(transforming growth factor β1,TGF-β1),誘導(dǎo)肝星狀細(xì)胞(hepatic stellate cells,HSCs)的激活,造成脂肪沉積和纖維化,最終驅(qū)動NAFLD發(fā)生

,甚至進(jìn)一步發(fā)生肝硬化和HCC.

2.5 cGAS-STING信號通路其他肝臟疾病 綜上所述,cGAS-STING也可能參與其他肝臟疾病發(fā)生發(fā)展過程,如肝纖維化、自身免疫性肝病和肝損傷

.有報道顯示,在NAFLD患者中,STING表達(dá)水平與肝纖維化程度呈正相關(guān),巨噬細(xì)胞中STING激活誘導(dǎo)TGF-b1釋放,從而刺激肝星狀細(xì)胞活化而導(dǎo)致纖維化.關(guān)于cGASSTING信號轉(zhuǎn)導(dǎo)和其他原因引起的肝纖維化的研究報道尚未出現(xiàn).因此,cGAS-STING信號通路參與肝纖維化發(fā)生和逆轉(zhuǎn)的機(jī)制也需要進(jìn)一步的研究.基于cGASSTING信號通路在固有免疫和適應(yīng)性免疫調(diào)節(jié)過程中的重要性,cGAS-STING信號通路可能與自身免疫性肝病密切相關(guān).近年來,cGAS和STING被發(fā)現(xiàn)參與肝臟酒精、輻射和缺血/再灌注(ischemia/reperfusion injury,IRI)等肝損傷相關(guān)進(jìn)程

.有研究證明

,酒精喂養(yǎng)的小鼠體內(nèi)表現(xiàn)出cGAS-STING信號水平的升高,這是因為酒精刺激使得內(nèi)質(zhì)網(wǎng)(endoplasmic reticulum,ER)應(yīng)激引發(fā)cGAS-STING通路激活和IRF3磷酸化,進(jìn)而導(dǎo)致肝細(xì)胞凋亡并伴有早期肝纖維化,而cGAS驅(qū)動的IRF3激活是通過肝細(xì)胞間的縫隙連接傳遞實現(xiàn)的,這個過程可加重肝損傷的程度.另一項研究報告稱

,cGAS敲除小鼠在IRI反應(yīng)中表現(xiàn)出更嚴(yán)重的肝損傷,而被STING siRNA轉(zhuǎn)染的小鼠表現(xiàn)出更低水平的肝損傷

.還有報道將IRI的改善歸因于cGAS對肝細(xì)胞自噬的誘導(dǎo)

.總的來說,cGAS-STING信號通路激活加劇炎癥和組織損傷的證據(jù)目前是充分的,但仍然需要進(jìn)一步研究cGAS是通過經(jīng)典細(xì)胞因子的產(chǎn)生加重組織損傷,還是通過自噬減輕組織損傷,以及哪種作用占主導(dǎo)地位.

3 cGAS-STING信號通路臨床應(yīng)用進(jìn)展

如前所述,激活cGAS-STING信號通路對肝病毒感染和腫瘤具有顯著的抑制作用,因此成為近年來肝病免疫學(xué)和腫瘤學(xué)領(lǐng)域的熱門靶點.目前,研究的重點主要集中在蛋白水平的臨床應(yīng)用靶向藥物,包括STING激動劑和抑制劑.在基因水平上的治療研究進(jìn)展主要集中在肝炎病毒,特別是HBV感染.有臨床研究報道稱cGAS-STING信號通路在肝癌放療免疫應(yīng)答的過程中發(fā)揮關(guān)鍵作用,放療誘導(dǎo)的外源DNA損傷可作為胞質(zhì)DNA激活cGASSTING信號通路,誘導(dǎo)產(chǎn)生IFN-Ⅰ,促進(jìn)放療效果

.此外,cGAS-STING信號通路激動劑還可以與免疫檢查點阻斷劑治療、CAR-T治療、溶瘤病毒治療等聯(lián)合使用

.當(dāng)然,最常見的臨床應(yīng)用研究是STING激動劑作為癌癥疫苗佐劑

,適當(dāng)?shù)氖褂每稍诳朔庖吣褪芎驮鰪?qiáng)腫瘤特異性免疫中起著重要作用.

1．1 一般資料 對2006－2011年在如東縣接受兒童系統(tǒng)管理的27 662例3個月內(nèi)小嬰兒聽力篩查資料進(jìn)行調(diào)查分析。

4 結(jié)論和展望

綜上所述,越來越多的證據(jù)表明cGAS-STING信號通路在多種肝臟疾病的發(fā)病機(jī)制中發(fā)揮重要作用.在乙型病毒性肝炎和HCC中,cGAS-STING信號通路抑制疾病進(jìn)展,激活該通路可顯著提高治療效果.而在ALD和NAFLD中該通路起促進(jìn)疾病進(jìn)展的作用.作為新發(fā)現(xiàn)的通路,cGAS-STING具有廣闊的臨床應(yīng)用前景,是治療研究的一個重要潛在方向,如何用好這把“雙刃劍”是我們要思考的問題.

1 Murthy AMV,Robinson N,Kumar S.Crosstalk between cGASSTING signaling and cell death.

2020;27:2989-3003 [PMID:32948836 DOI:10.1038/s41418-020-00624-8]

2 Bai J,Liu F.The cGAS-cGAMP-STING Pathway:A Molecular Link Between Immunity and Metabolism.

2019;68:1099-1108 [PMID:31109939 DOI:10.2337/dbi18-0052]

3 Motwani M,Pesiridis S,Fitzgerald KA.DNA sensing by the cGAS-STING pathway in health and disease.

2019;20:657-674 [PMID:31358977 DOI:10.1038/s41576-019-0151-1]

4 Dansako H,Imai H,Ueda Y,Satoh S,Shimotohno K,Kato N.High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction.

2019;1:67-80[PMID:32123822 DOI:10.1096/fba.1022]

5 Luo X,Li H,Ma L,Zhou J,Guo X,Woo SL,Pei Y,Knight LR,Deveau M,Chen Y,Qian X,Xiao X,Li Q,Chen X,Huo Y,McDaniel K,Francis H,Glaser S,Meng F,Alpini G,Wu C.Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice.

2018;155:1971-1984.e4 [PMID:30213555 DOI:10.1053/j.gastr.2018.09.010]

6 Du S,Chen G,Yuan B,Hu Y,Yang P,Chen Y,Zhao Q,Zhou J,Fan J,Zeng Z.DNA sensing and associated type 1 interferon signaling contributes to progression of radiation-induced liver injury.

2021;18:1718-1728 [PMID:32203191 DOI:10.1038/s4143-020-0395-x]

7 Thomsen MK,Skouboe MK,Boularan C,Vernejoul F,Lioux T,Leknes SL,Berthelsen MF,Riedel M,Cai H,Joseph JV,Perouzel E,Tiraby M,Vendelbo MH,Paludan SR.The cGASSTING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma.

2020;39:1652-1664 [PMID:31740782 DOI:10.1038/s41388-019-1108-8]

8 劉剛,劉芳,向慧玲,張亞蘋,史利利,葉青,呂洪敏,梁靜.直接抗病毒藥物治療慢性丙型肝炎48周臨床觀察.世界華人消化雜志2022;30:49-55 [DOI:10.11569/wcjd.v30.i1.49]

9 Li XD,Wu J,Gao D,Wang H,Sun L,Chen ZJ.Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects.

2013;341:1390-1394 [PMID:23989956 DOI:10.1126/science.1244040]

10 Paijo J,D?ring M,Spanier J,Grabski E,Nooruzzaman M,Schmidt T,Witte G,Messerle M,Hornung V,Kaever V,Kalinke U.cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells.

2016;12:e1005546 [PMID:27058035 DOI:10.1371/journalppat.1005546]

11 Schoggins JW,MacDuff DA,Imanaka N,Gainey MD,Shrestha B,Eitson JL,Mar KB,Richardson RB,Ratushny AV,Litvak V,Dabelic R,Manicassamy B,Aitchison JD,Aderem A,Elliott RM,García-Sastre A,Racaniello V,Snijder EJ,Yokoyama WM,Diamond MS,Virgin HW,Rice CM.Pan-viral specificity of IFNinduced genes reveals new roles for cGAS in innate immunity.

2014;505:691-695 [PMID:24284630 DOI:10.103/nature12862]

12 Verrier ER,Yim SA,Heydmann L,El Saghire H,Bach C,Turon-Lagot V,Mailly L,Durand SC,Lucifora J,Durantel D,Pessaux P,Manel N,Hirsch I,Zeisel MB,Pochet N,Schuster C,Baumert TF.Hepatitis B Virus Evasion From Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Sensing in Human Hepatocytes.

2018;68:1695-1709 [PMID:29679386 DOI:10.102/hep.30054]

13 Guo F,Han Y,Zhao X,Wang J,Liu F,Xu C,Wei L,Jiang JD,Block TM,Guo JT,Chang J.STING agonists induce an innate antiviral immune response against hepatitis B virus.

2015;59:1273-1281 [PMID:25512416 DOI:10.1128/AC.04321-14]

14 He J,Hao R,Liu D,Liu X,Wu S,Guo S,Wang Y,Tien P,Guo D.Inhibition of hepatitis B virus replication by activation of the cGAS-STING pathway.

2016;97:3368-3378 [PMID:27902332 DOI:10.1099jgv.0.000647]

15 Lauterbach-Rivière L,Bergez M,M?nch S,Qu B,Riess M,Vondran FWR,Liese J,Hornung V,Urban S,K?nig R.Hepatitis B Virus DNA is a Substrate for the cGAS/STING Pathway but is not Sensed in Infected Hepatocytes.

2020;12 [PMID:32485908 DOI:10.390/v12060592]

16 Guo F,Tang L,Shu S,Sehgal M,Sheraz M,Liu B,Zhao Q,Cheng J,Zhao X,Zhou T,Chang J,Guo JT.Activation of Stimulator of Interferon Genes in Hepatocytes Suppresses the Replication of Hepatitis B Virus.

2017;61 [PMID:28717041 DOI:10.1128AAC.00771-17]

17 Li M,Sun R,Xu L,Yin W,Chen Y,Zheng X,Lian Z,Wei H,Tian Z.Kupffer Cells Support Hepatitis B Virus-Mediated CD8+T Cell Exhaustion via Hepatitis B Core Antigen-TLR2 Interactions in Mice.

2015;195:3100-3109 [PMID:26304988 DOI:10.4049/jimunol.1500839]

18 Sun W,Li Y,Chen L,Chen H,You F,Zhou X,Zhou Y,Zhai Z,Chen D,Jiang Z.ERIS,an endoplasmic reticulum IFN stimulator,activates innate immune signaling through dimerization.

2009;106:8653-8658 [PMID:19433799 DOI:10.1073/pnas.0900850106]

19 Zhong B,Yang Y,Li S,Wang YY,Li Y,Diao F,Lei C,He X,Zhang L,Tien P,Shu HB.The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation.

2008;29:538-550 [PMID:18818105 DOI:10.1016/j.immuni.2008.09.003]

20 Tanaka Y,Chen ZJ.STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.

2012;5:ra20 [PMID:22394562 DOI:10.1126/scisignal.2002521]

21 Saitoh T,Fujita N,Hayashi T,Takahara K,Satoh T,Lee H,Matsunaga K,Kageyama S,Omori H,Noda T,Yamamoto N,Kawai T,Ishii K,Takeuchi O,Yoshimori T,Akira S.Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response.

2009;106:20842-20846 [PMID:19926846 DOI:10.1073/pnas.0911267106]

22 Nagy LE.The Role of Innate Immunity in Alcoholic Liver Disease.

2015;37:237-250 [PMID:26695748]

23 Luther J,Khan S,Gala MK,Kedrin D,Sridharan G,Goodman RP,Garber JJ,Masia R,Diagacomo E,Adams D,King KR,Piaker S,Reinecker HC,Yarmush ML,Argemi J,Bataller R,Dienstag JL,Chung RT,Patel SJ.Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation.

2020;117:11667-11673 [PMID:32393626 DOI:10.1073/pns.1911870117]

24 Segretain D,Falk MM.Regulation of connexin biosynthesis,assembly,gap junction formation,and removal.

2004;1662:3-21 [PMID:15033576 DOI:10.1016/j.bbame.2004.01.007]

25 Ablasser A,Schmid-Burgk JL,Hemmerling I,Horvath GL,Schmidt T,Latz E,Hornung V.Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP.

2013;503:530-534 [PMID:24077100 DOI:10.103/nature12640]

26 吳錦婷,賀博武,曹婕露,嚴(yán)峻彬,陳芝蕓.STING信號通路參與NAFLD的研究進(jìn)展.世界華人消化雜志 2021;29:1396-1401[DOI:10.11569/wcjd.v29.i24.1396]

27 Yki-J?rvinen H.Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome.

2014;2:901-910 [PMID:24731669 DOI:10.1016/S2213-8587(14)70032-4]

28 Papatheodoridi AM,Chrysavgis L,Koutsilieris M,Chatzigeorgiou A.The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis.

2020;71:363-374 [PMID:31230380 DOI:10.102/hep.30834]

29 Sze A,Belgnaoui SM,Olagnier D,Lin R,Hiscott J,van Grevenynghe J.Host restriction factor SAMHD1 limits human T cell leukemia virus type 1 infection of monocytes via STINGmediated apoptosis.

2013;14:422-434 [PMID:24139400 DOI:10.1016/j.chom.2013.09.009]

30 Petrasek J,Iracheta-Vellve A,Csak T,Satishchandran A,Kodys K,Kurt-Jones EA,Fitzgerald KA,Szabo G.STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease.

2013;110:16544-16549 [PMID:24052526 DOI:10.1073/pns.1308331110]

31 Wang X,Rao H,Zhao J,Wee A,Li X,Fei R,Huang R,Wu C,Liu F,Wei L.STING expression in monocyte-derived macrophages is associated with the progression of liver inflammation and fibrosis in patients with nonalcoholic fatty liver disease.

2020;100:542-552 [PMID:31745210 DOI:10.1038/s4374-019-0346]

32 Qiao JT,Cui C,Qing L,Wang LS,He TY,Yan F,Liu FQ,Shen YH,Hou XG,Chen L.Activation of the STING-IRF3 pathway promotes hepatocyte inflammation,apoptosis and induces metabolic disorders in nonalcoholic fatty liver disease.

2018;81:13-24 [PMID:29106945 DOI:10.1016/j.metabo.2017.09.010]

33 秦建民.原發(fā)性肝癌轉(zhuǎn)化治療指征與選擇策略.世界華人消化雜志 2021;29:501-510 [DOI:10.11569/wcjd.v29.i10.501]

34 Ranoa DRE,Widau RC,Mallon S,Parekh AD,Nicolae CM,Huang X,Bolt MJ,Arina A,Parry R,Kron SJ,Moldovan GL,Khodarev NN,Weichselbaum RR.STING Promotes Homeostasis via Regulation of Cell Proliferation and Chromosomal Stability.

2019;79:1465-1479 [PMID:30482772 DOI:10.1158/0008-547.can-18-1972]

35 Papewalis C,Jacobs B,Wuttke M,Ullrich E,Baehring T,Fenk R,Willenberg HS,Schinner S,Cohnen M,Seissler J,Zacharowski K,Scherbaum WA,Schott M.IFN-alpha skews monocytes into CD56+-expressing dendritic cells with potent functional activities in vitro and in vivo.

2008;180:1462-1470[PMID:18209041 DOI:10.4049/jimmunl.180.3.1462]

36 Chen B,Rao X,Wang X,Luo Z,Wang J,Sheng S,Liu Y,Zhang N,Jin S,Chen H,Sun C,Xu T,Du Y.cGAS-STING Signaling Pathway and Liver Disease:From Basic Research to Clinical Practice.

2021;12:719644 [PMID:34483930 DOI:10.3389/fphar.2021.719644]

37 Qi Z,Yan F,Chen D,Xing W,Li Q,Zeng W,Bi B,Xie J.Identification of prognostic biomarkers and correlations with immune infiltrates among cGAS-STING in hepatocellular carcinoma.

2020;40 [PMID:33006365 DOI:10.1042/BSR20202603]

38 Wang X,Rao H,Zhao J,Wee A,Li X,Fei R,Huang R,Wu C,Liu F,Wei L.STING expression in monocyte-derived macrophages is associated with the progression of liver inflammation and fibrosis in patients with nonalcoholic fatty liver disease.

2020;100:542-552 [PMID:31745210 DOI:10.1038/s41374-019-0342-6]

39 Luedde T,Schwabe RF.NF-κB in the liver--linking injury,fibrosis and hepatocellular carcinoma.

2011;8:108-118 [PMID:21293511 DOI:10.1038/nrgastro.2010.213]

40 Chen R,Du J,Zhu H,Ling Q.The role of cGAS-STING signalling in liver diseases.

2021;3:100324 [PMID:34381984 DOI:10.1016/j.jhepr.2021.100324]

41 Petrasek J,Iracheta-Vellve A,Csak T,Satishchandran A,Kodys K,Kurt-Jones EA,Fitzgerald KA,Szabo G.STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease.

2013;110:16544-16549 [PMID:24052526 DOI:10.1073/pnas.1308331110]

42 Iracheta-Vellve A,Petrasek J,Gyongyosi B,Satishchandran A,Lowe P,Kodys K,Catalano D,Calenda CD,Kurt-Jones EA,Fitzgerald KA,Szabo G.Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes.

2016;291:26794-26805 [PMID:27810900 DOI:10.1074/jbc.M116.736991]

43 Lei Z,Deng M,Yi Z,Sun Q,Shapiro RA,Xu H,Li T,Loughran PA,Griepentrog JE,Huang H,Scott MJ,Huang F,Billiar TR.cGAS-mediated autophagy protects the liver from ischemiareperfusion injury independently of STING.

2018;314:G655-G667 [PMID:29446653 DOI:10.1152/ajpgi.00326.2017]

44 Shen A,Zheng D,Luo Y,Mou T,Chen Q,Huang Z,Wu Z.MicroRNA-24-3p alleviates hepatic ischemia and reperfusion injury in mice through the repression of STING signaling.

2020;522:47-52 [PMID:31735332 DOI:10.1016/j.bbrc.2019.10.182]

45 Wang C,Sun Z,Zhao C,Zhang Z,Wang H,Liu Y,Guo Y,Zhang B,Gu L,Yu Y,Hu Y,Wu J.Maintaining manganese in tumor to activate cGAS-STING pathway evokes a robust abscopal antitumor effect.

2021;331:480-490 [PMID:33545219 DOI:10.1016/j.jconrel.2021.01.036]

46 Waidmann O.Recent developments with immunotherapy for hepatocellular carcinoma.

2018;18:905-910[PMID:29995439 DOI:10.1080/14712598.2018.1499722]

47 Xie Y,Xiang Y,Sheng J,Zhang D,Yao X,Yang Y,Zhang X.Immunotherapy for Hepatocellular Carcinoma:Current Advances and Future Expectations.

2018;2018:8740976 [PMID:29785403 DOI:10.1155/2018/8740976]