IRE1α/TRAF2/JNK信号通路在急性肝衰竭发展中的作用机制及潜在价值

关海梅; 张衎; 陈玮钰; 李国宝; 曾阳玲; 张日云; 王恬雯; 谢宝华; 毛德文

doi:10.12449/JCH240633

IRE1α/TRAF2/JNK信号通路在急性肝衰竭发展中的作用机制及潜在价值

DOI: 10.12449/JCH240633

1.
广西中医药大学研究生院，南宁 530001
2.
广西中医药大学第一附属医院肝病科，南宁 530023

基金项目:

国家自然科学基金 (82274434);

国家自然科学基金 (81960841);

国家自然科学基金 (82060848);

广西中医药大学研究生教育创新计划 (YCBZ2023157)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：关海梅负责拟定写作思路并撰写文章；陈玮钰、曾阳玲负责设计论文框架；李国宝、张日云负责收集、整理相关文献；王恬雯、谢宝华负责修订论文；毛德文、张衎提供指导意见并最后定稿。

详细信息

通信作者:
毛德文， mdwboshi2005@163.com （ORCID： 0000-0001-9438-9325）

计量
- 文章访问数: 239
- HTML全文浏览量: 157
- PDF下载量: 28
- 被引次数: 0
出版历程
- 收稿日期: 2023-11-15
- 录用日期: 2024-01-18
- 出版日期: 2024-06-25

Mechanism of action and potential value of the IRE1α/TRAF2/JNK pathway in the progression of acute liver failure

1.
Graduate School，Guangxi University of Chinese Medicine，Nanning 530001，China
2.
Department of Hepatology，The First Affiliated Hospital of Guangxi University of Chinese Medicine，Nanning 530023，China

Research funding:

National Natural Science Foundation of China (82274434);

National Natural Science Foundation of China (81960841);

National Natural Science Foundation of China (82060848);

Guangxi University of Traditional Chinese Medicine Graduate Education Innovation Program (YCBZ2023157)

More Information

Corresponding author: MAO Dewen， mdwboshi2005@163.com （ORCID： 0000-0001-9438-9325）

摘要

摘要: 急性肝衰竭（ALF）是临床上最危重的一种肝脏疾病，严重影响我国人民生命健康。由于ALF的发病率和死亡率高、发病机制不明确、治疗手段有限，成为肝病领域亟待解决的重大难题。近年来，越来越多研究表明，内质网应激是ALF进展中一个关键的生物学过程，IRE1α/TRAF2/JNK通路作为内质网应激信号传导的一部分，在疾病的发展中发挥着放大炎症反应、促进肝细胞凋亡、抑制肝再生能力等作用。而中医药作为我国传统瑰宝，从中药单体中寻找有效防治ALF的药物成为研究热点。本文旨在通过阐述IRE1α/TRAF2/JNK通路在ALF发展中的作用机制，以及总结红景天苷、楮实子、补骨脂+五味子、黄芩素、京尼平、山柰酚、白藜芦醇、沙棘多糖提取物、木犀草素等中药单体调控该通路的潜在价值，以期为ALF的进一步研究和临床实践提供参考依据。
- 肝功能衰竭，急性 /
- 信号传导 /
- 内质网应激
Abstract: Acute liver failure （ALF） is one of the most critical liver diseases in clinical practice and seriously affects the life and health of Chinese people. Due to its high morbidity and mortality rates， unclear pathogenesis， and limited treatment methods， ALF has become a major problem that needs to be solved urgently in the field of liver diseases. In recent years， more and more studies have shown that endoplasmic reticulum stress is a key biological process in the progression of ALF， and the IRE1α/TRAF2/JNK pathway， as a part of endoplasmic reticulum stress signaling， plays a role in amplifying inflammatory response， promoting hepatocyte apoptosis， and inhibiting liver regeneration ability during the progression of diseases. As a traditional treasure of China， traditional Chinese medicine has become a research hotspot in search for effective prevention and treatment drugs for ALF from monomers of Chinese herbs. This article elaborates on the mechanism of action of the IRE1α/TRAF2/JNK pathway in the progression of ALF and summarizes the potential value of several monomers of Chinese herbs in regulating this pathway， such as salidroside， Fructus Broussonetiae， Fructus Psoraleae+Schisandra chinensis， baicalein， genipin， kaempferol， resveratrol， sea buckthorn polysaccharide extract， and luteol， in order to provide a reference for further research and clinical practice of ALF.
- Liver Failure， Acute /
- Signal Transduction /
- Endoplasmic Reticulum Stress

HTML全文

参考文献(71)

[1]	LIN DN, CHEN H, XIONG J, et al. Mesenchymal stem cells exosomal let-7a-5p improve autophagic flux and alleviate liver injury in acute-on-chronic liver failure by promoting nuclear expression of TFEB[J]. Cell Death Dis, 2022, 13( 10): 865. DOI: 10.1038/s41419-022-05303-9.
[2]	Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association; Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Guideline for diagnosis and treatment of liver failure[J]. J Clin Hepatol, 2019, 35( 1): 38- 44. DOI: 10.3969/j.issn.1001-5256.2019.01.007. 中华医学会感染病学分会肝衰竭与人工肝学组, 中华医学会肝病学分会重型肝病与人工肝学组. 肝衰竭诊治指南(2018年版)[J]. 临床肝胆病杂志, 2019, 35( 1): 38- 44. DOI: 10.3969/j.issn.1001－5256.2019.01.007.
[3]	WLODZIMIROW KA, ESLAMI S, ABU-HANNA A, et al. Systematic review: Acute liver failure-one disease, more than 40 definitions[J]. Aliment Pharmacol Ther, 2012, 35( 11): 1245- 1256. DOI: 10.1111/j.1365-2036.2012.05097.x.
[4]	LI N, GU H, ZHU Y, et al. Recent progresses of the treatment of liver failure[J]. Med Philos B, 2018, 39( 8): 50- 54. DOI: 10.12014/j.issn.1002-0772.2018.08b.15. 李娜, 顾欢, 朱英, 等. 肝衰竭治疗的最新进展[J]. 医学与哲学·B, 2018, 39( 8): 50- 54. DOI: 10.12014/j.issn.1002-0772.2018.08b.15.
[5]	MEZZANO G, JUANOLA A, CARDENAS A, et al. Global burden of disease: Acute-on-chronic liver failure, a systematic review and meta-analysis[J]. Gut, 2022, 71( 1): 148- 155. DOI: 10.1136/gutjnl-2020-322161.
[6]	YE YN, GAO ZL. Three attacks in the development of HBV-related liver failure[J]. Infect Dis Inf, 2009, 22( 5): 276- 279. DOI: 10.3969/j.issn.1007-8134.2009.05.006. 叶一农, 高志良. 乙型肝炎肝衰竭发生机制中的三重打击[J]. 传染病信息, 2009, 22( 5): 276- 279. DOI: 10.3969/j.issn.1007-8134.2009.05.006.
[7]	AJOOLABADY A, KAPLOWITZ N, LEBEAUPIN C, et al. Endoplasmic reticulum stress in liver diseases[J]. Hepatology, 2023, 77( 2): 619- 639. DOI: 10.1002/hep.32562.
[8]	TORRES S, BAULIES A, INSAUSTI-URKIA N, et al. Endoplasmic reticulum stress-induced upregulation of STARD1 promotes acetaminophen-induced acute liver failure[J]. Gastroenterology, 2019, 157( 2): 552- 568. DOI: 10.1053/j.gastro.2019.04.023.
[9]	PRINZ E, AVIRAM S, ARONHEIM A. WDR62 mediates TNFα-dependent JNK activation via TRAF2-MLK3 axis[J]. Mol Biol Cell, 2018, 29( 20): 2470- 2480. DOI: 10.1091/mbc.E17-08-0504.
[10]	TABAS I, RON D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress[J]. Nat Cell Biol, 2011, 13( 3): 184- 190. DOI: 10.1038/ncb0311-184.
[11]	PLÜMPE J, MALEK NP, BOCK CT, et al. NF-kappaB determines between apoptosis and proliferation in hepatocytes during liver regeneration[J]. Am J Physiol Gastrointest Liver Physiol, 2000, 278( 1): G173- G183. DOI: 10.1152/ajpgi.2000.278.1.G173.
[12]	CZAJA MJ. The future of GI and liver research: Editorial perspectives. III. JNK/AP-1 regulation of hepatocyte death[J]. Am J Physiol Gastrointest Liver Physiol, 2003, 284( 6): G875- G879. DOI: 10.1152/ajpgi.00549.2002.
[13]	LIU W, JING ZT, WU SX, et al. PI3K/AKT inhibitors promote death receptor-mediated hepatocyte apoptosis and liver injury[C]// The Chinese Society of Biochemistry and Molecular Biology. Abstract Collection of the12th National Congress of theChinese Society of Biochemistry and Molecular Biology and the 2018 National Academic Conference. Chongqing, 2018: 113- 114. 刘伟, 荆振唐, 吴淑香, 等. PI₃K/akt抑制剂促进死亡受体介导的肝细胞凋亡及肝损伤[C]// 中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议摘要集. 重庆, 2018: 113- 114.
[14]	HEINRICHSDORFF J, LUEDDE T, PERDIGUERO E, et al. p38 alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure[J]. EMBO Rep, 2008, 9( 10): 1048- 1054. DOI: 10.1038/embor.2008.149.
[15]	WANG KY, WEI DH, ZOU ZL, et al. Changes of MPO and Nrf2/HO-1 signaling pathway in D-GalN/LPS-induced acute liver failure in rats[J]. Chin J Crit Care Med, 2022, 42( 8): 717- 722. DOI: 10.3969/j.issn.1002-1949.2022.08.012. 王柯尹, 魏大海, 邹卓林, 等. D-GalN/LPS诱导大鼠ALF中髓过氧化物酶和Nrf2/HO-1信号通路的变化[J]. 中国急救医学, 2022, 42( 8): 717- 722. DOI: 10.3969/j.issn.1002-1949.2022.08.012.
[16]	XU CY, BAILLY-MAITRE B, REED JC. Endoplasmic reticulum stress: Cell life and death decisions[J]. J Clin Invest, 2005, 115( 10): 2656- 2664. DOI: 10.1172/JCI26373.
[17]	LISBONA F, ROJAS-RIVERA D, THIELEN P, et al. BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha[J]. Mol Cell, 2009, 33( 6): 679- 691. DOI: 10.1016/j.molcel.2009.02.017.
[18]	URANO F, WANG X, BERTOLOTTI A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1[J]. Science, 2000, 287( 5453): 664- 666. DOI: 10.1126/science.287.5453.664.
[19]	XIE YC, RAMACHANDRAN A, BRECKENRIDGE DG, et al. Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury[J]. Toxicol Appl Pharmacol, 2015, 286( 1): 1- 9. DOI: 10.1016/j.taap.2015.03.019.
[20]	WANG CF, CHEN K, XIA YJ, et al. N-acetylcysteine attenuates ischemia-reperfusion-induced apoptosis and autophagy in mouse liver via regulation of the ROS/JNK/Bcl-2 pathway[J]. PLoS One, 2014, 9( 9): e108855. DOI: 10.1371/journal.pone.0108855.
[21]	BRENNER C, GALLUZZI L, KEPP O, et al. Decoding cell death signals in liver inflammation[J]. J Hepatol, 2013, 59( 3): 583- 594. DOI: 10.1016/j.jhep.2013.03.033.
[22]	ROTHE M, SARMA V, DIXIT VM, et al. TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40[J]. Science, 1995, 269( 5229): 1424- 1427. DOI: 10.1126/science.7544915.
[23]	SEKI E, BRENNER DA, KARIN M. A liver full of JNK: Signaling in regulation of cell function and disease pathogenesis, and clinical approaches[J]. Gastroenterology, 2012, 143( 2): 307- 320. DOI: 10.1053/j.gastro.2012.06.004.
[24]	HANAWA N, SHINOHARA M, SABERI B, et al. Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury[J]. J Biol Chem, 2008, 283( 20): 13565- 13577. DOI: 10.1074/jbc.M708916200.
[25]	REN F, YANG BZ, ZHANG XY, et al. Role of endoplasmic reticulum stress in D-GalN/LPS-induced acute liver failure[J]. Chin J Hepatol, 2014, 22( 5): 364- 368. DOI: 10.3760/cma.j.issn.1007-3418.2014.05.009. 任锋, 杨丙章, 张向颖, 等. 内质网应激在D-氨基半乳糖/脂多糖诱导小鼠急性肝衰竭中的作用[J]. 中华肝脏病杂志, 2014, 22( 5): 364- 368. DOI: 10.3760/cma.j.issn.1007-3418.2014.05.009.
[26]	RIAZ TA, JUNJAPPA RP, HANDIGUND M, et al. Role of endoplasmic reticulum stress sensor IRE1α in cellular physiology, calcium, ROS signaling, and metaflammation[J]. Cells, 2020, 9( 5): 1160. DOI: 10.3390/cells9051160.
[27]	KARAGÖZ GE, ACOSTA-ALVEAR D, NGUYEN HT, et al. An unfolded protein-induced conformational switch activates mammalian IRE1[J]. eLife, 2017, 6: e30700. DOI: 10.7554/eLife.30700.
[28]	LEE KP, DEY M, NECULAI D, et al. Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing[J]. Cell, 2008, 132( 1): 89- 100. DOI: 10.1016/j.cell.2007.10.057.
[29]	MA K, VATTEM KM, WEK RC. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress[J]. J Biol Chem, 2002, 277( 21): 18728- 18735. DOI: 10.1074/jbc.M200903200.
[30]	YE RS, JUNG DY, JUN JY, et al. Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance[J]. Diabetes, 2010, 59( 1): 6- 16. DOI: 10.2337/db09-0755.
[31]	INABA Y, FURUTANI T, KIMURA K, et al. Growth arrest and DNA damage-inducible 34 regulates liver regeneration in hepatic steatosis in mice[J]. Hepatology, 2015, 61( 4): 1343- 1356. DOI: 10.1002/hep.27619.
[32]	WU J, HE GT, ZHANG WJ, et al. IRE1α signaling pathways involved in mammalian cell fate determination[J]. Cell Physiol Biochem, 2016, 38( 3): 847- 858. DOI: 10.1159/000443039.
[33]	HUR KY, SO JS, RUDA V, et al. IRE1α activation protects mice against acetaminophen-induced hepatotoxicity[J]. J Exp Med, 2012, 209( 2): 307- 318. DOI: 10.1084/jem.20111298.
[34]	HAN D, LERNER AG, VANDE WALLE L, et al. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates[J]. Cell, 2009, 138( 3): 562- 575. DOI: 10.1016/j.cell.2009.07.017.
[35]	AHYI AN, QUINTON LJ, JONES MR, et al. Roles of STAT3 in protein secretion pathways during the acute-phase response[J]. Infect Immun, 2013, 81( 5): 1644- 1653. DOI: 10.1128/IAI.01332-12.
[36]	DUVIGNEAU JC, LUÍS A, GORMAN AM, et al. Crosstalk between inflammatory mediators and endoplasmic reticulum stress in liver diseases[J]. Cytokine, 2019, 124: 154577. DOI: 10.1016/j.cyto.2018.10.018.
[37]	LI YK, SCHWABE RF, DEVRIES-SEIMON T, et al. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: Model of NF-kappaB-and map kinase-dependent inflammation in advanced atherosclerosis[J]. J Biol Chem, 2005, 280( 23): 21763- 21772. DOI: 10.1074/jbc.M501759200.
[38]	RASHID HO, KIM HK, JUNJAPPA R, et al. Endoplasmic reticulum stress in the regulation of liver diseases: Involvement of Regulated IRE1α and β-dependent decay and miRNA[J]. J Gastroenterol Hepatol, 2017, 32( 5): 981- 991. DOI: 10.1111/jgh.13619.
[39]	QI ZH, CHEN LX. Endoplasmic reticulum stress and autophagy[J]. Adv Exp Med Biol, 2019, 1206: 167- 177. DOI: 10.1007/978-981-15-0602-4_8.
[40]	LERNER AG, UPTON JP, PRAVEEN PVK, et al. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress[J]. Cell Metab, 2012, 16( 2): 250- 264. DOI: 10.1016/j.cmet.2012.07.007.
[41]	ZINDEL J, KUBES P. DAMPs, PAMPs, and LAMPs in immunity and sterile inflammation[J]. Annu Rev Pathol, 2020, 15: 493- 518. DOI: 10.1146/annurev-pathmechdis-012419-032847.
[42]	TANG Y, ZHOU XP, CAO T, et al. Endoplasmic reticulum stress and oxidative stress in inflammatory diseases[J]. DNA Cell Biol, 2022, 41( 11): 924- 934. DOI: 10.1089/dna.2022.0353.
[43]	XU HX, TIAN Y, TANG DM, et al. An endoplasmic reticulum stress-MicroRNA-26a feedback circuit in NAFLD[J]. Hepatology, 2021, 73( 4): 1327- 1345. DOI: 10.1002/hep.31428.
[44]	NÜRNBERGER S, MILLER I, DUVIGNEAU JC, et al. Impairment of endoplasmic reticulum in liver as an early consequence of the systemic inflammatory response in rats[J]. Am J Physiol Gastrointest Liver Physiol, 2012, 303( 12): G1373- G1383. DOI: 10.1152/ajpgi.00056.2012.
[45]	HIRAMATSU N, KASAI A, HAYAKAWA K, et al. Real-time detection and continuous monitoring of ER stress in vitro and in vivo by ES-TRAP: Evidence for systemic, transient ER stress during endotoxemia[J]. Nucleic Acids Res, 2006, 34( 13): e93. DOI: 10.1093/nar/gkl515.
[46]	TAM AB, KOONG AC, NIWA M. Ire1 has distinct catalytic mechanisms for XBP1/HAC1 splicing and RIDD[J]. Cell Rep, 2014, 9( 3): 850- 858. DOI: 10.1016/j.celrep.2014.09.016.
[47]	ZHANG KZ, SHEN XH, WU J, et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response[J]. Cell, 2006, 124( 3): 587- 599. DOI: 10.1016/j.cell.2005.11.040.
[48]	MAUREL M, SAMALI A, CHEVET E. Endoplasmic reticulum stress: At the crossroads of inflammation and metabolism in hepatocellular carcinoma development[J]. Cancer Cell, 2014, 26( 3): 301- 303. DOI: 10.1016/j.ccr.2014.08.007.
[49]	BROZZI F, NARDELLI TR, LOPES M, et al. Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms[J]. Diabetologia, 2015, 58( 10): 2307- 2316. DOI: 10.1007/s00125-015-3669-6.
[50]	ZHAN F, ZHAO GP, LI X, et al. Inositol-requiring enzyme 1 alpha endoribonuclease specific inhibitor STF-083010 protects the liver from thioacetamide-induced oxidative stress, inflammation and injury by triggering hepatocyte autophagy[J]. Int Immunopharmacol, 2019, 73: 261- 269. DOI: 10.1016/j.intimp.2019.04.051.
[51]	LEI Y, WANG SL, REN BS, et al. CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy[J]. PLoS One, 2017, 12( 8): e0183680. DOI: 10.1371/journal.pone.0183680.
[52]	TIAN RD, CHEN YQ, HE YH, et al. Phosphorylation of eIF2α mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury[J]. Ann Hepatol, 2020, 19( 1): 79- 87. DOI: 10.1016/j.aohep.2019.05.008.
[53]	WANG S, LUAN JJ, LV XW. Inhibition of endoplasmic reticulum stress attenuated ethanol-induced exosomal miR-122 and acute liver injury in mice[J]. Alcohol Alcohol, 2019, 54( 5): 465- 471. DOI: 10.1093/alcalc/agz058.
[54]	WANG XF, ZHANG X, WANG F, et al. FGF1 protects against APAP-induced hepatotoxicity via suppression of oxidative and endoplasmic reticulum stress[J]. Clin Res Hepatol Gastroenterol, 2019, 43( 6): 707- 714. DOI: 10.1016/j.clinre.2019.03.006.
[55]	QI J, CHEN X, ZHANG C, et al. Effects of 4-phenylbutyric acid on carbon tetrachloride-induced acute liver injury in mice[J]. Chin J Hepatol, 2015, 23( 4): 286- 291. DOI: 10.3760/cma.j.issn.1007-3418.2015.04.011. 齐军, 陈熙, 张程, 等. 4-苯基丁酸对四氯化碳诱导小鼠急性肝损伤的影响[J]. 中华肝脏病杂志, 2015, 23( 4): 286- 291. DOI: 10.3760/cma.j.issn.1007-3418.2015.04.011.
[56]	LI WY, YANG F, LI X, et al. Stress granules inhibit endoplasmic reticulum stress-mediated apoptosis during hypoxia-induced injury in acute liver failure[J]. World J Gastroenterol, 2023, 29( 8): 1315- 1329. DOI: 10.3748/wjg.v29.i8.1315.
[57]	ABO-ZAID OA, MOAWED FS, ISMAIL ES, et al. β-Sitosterol mitigates hepatocyte apoptosis by inhibiting endoplasmic reticulum stress in thioacetamide-induced hepatic injury in γ-irradiated rats[J]. Food Chem Toxicol, 2023, 172: 113602. DOI: 10.1016/j.fct.2023.113602.
[58]	DESHMUKH K, APTE U. The role of endoplasmic reticulum stress response in liver regeneration[J]. Semin Liver Dis, 2023, 43( 3): 279- 292. DOI: 10.1055/a-2129-8977.
[59]	ALHUTHALI HM, BRADSHAW TD, LIM KH, et al. The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun[J]. BMC Cancer, 2020, 20( 1): 629. DOI: 10.1186/s12885-020-07119-2.
[60]	HUANG CC, WANG JM, KIKKAWA U, et al. Calcineurin-mediated dephosphorylation of c-Jun Ser-243 is required for c-Jun protein stability and cell transformation[J]. Oncogene, 2008, 27( 17): 2422- 2429. DOI: 10.1038/sj.onc.1210888.
[61]	CHEN XG, LV QX, MA J, et al. PLCγ2 promotes apoptosis while inhibits proliferation in rat hepatocytes through PKCD/JNK MAPK and PKCD/p38 MAPK signalling[J]. Cell Prolif, 2018, 51( 3): e12437. DOI: 10.1111/cpr.12437.
[62]	KHAMPHAYA T, CHUKIJRUNGROAT N, SAENGSIRISUWAN V, et al. Nonalcoholic fatty liver disease impairs expression of the type II inositol 1, 4, 5-trisphosphate receptor[J]. Hepatology, 2018, 67( 2): 560- 574. DOI: 10.1002/hep.29588.
[63]	XIONG YL, WANG YM, XIONG YL, et al. Salidroside alleviated hypoxia-induced liver injury by inhibiting endoplasmic reticulum stress-mediated apoptosis via IRE1α/JNK pathway[J]. Biochem Biophys Res Commun, 2020, 529( 2): 335- 340. DOI: 10.1016/j.bbrc.2020.06.036.
[64]	GAO JM, WANG TT, BIAO YN, et al. Broussonetiae fructus protects against APAP-induced liver injury in mice by inhibiting endoplasmic reticulum stress pathway[J]. Chin J Exp Tradit Med Formulae, 2022, 28( 16): 66- 73. DOI: 10.13422/j.cnki.syfjx.20221544. 高晶淼, 王婷婷, 彪雅宁, 等. 楮实子通过抑制ERS途径保护APAP诱导的小鼠肝损伤[J]. 中国实验方剂学杂志, 2022, 28( 16): 66- 73. DOI: 10.13422/j.cnki.syfjx.20221544.
[65]	ZHANG JX, YIN J, QU XL, et al. Effects of compatibility of Schisandra chinensis on Psoralea corylifolia-induced oxidative damage and endoplasmic reticulum stress in hepatocytes[J]. China Pharm, 2022, 33( 9): 1088- 1093. DOI: 10.6039/j.issn.1001-0408.2022.09.11. 张婧茜, 殷佳, 曲晓琳, 等. 五味子配伍对补骨脂致肝细胞氧化损伤和ERS的影响[J]. 中国药房, 2022, 33( 9): 1088- 1093. DOI: 10.6039/j.issn.1001-0408.2022.09.11.
[66]	WU YL, LIAN LH, WAN Y, et al. Baicalein inhibits nuclear factor-κB and apoptosis via c-FLIP and MAPK in D-GalN/LPS induced acute liver failure in murine models[J]. Chem Biol Interact, 2010, 188( 3): 526- 534. DOI: 10.1016/j.cbi.2010.09.008.
[67]	KIM SJ, KIM JK, LEE DU, et al. Genipin protects lipopolysaccharide-induced apoptotic liver damage in D-galactosamine-sensitized mice[J]. Eur J Pharmacol, 2010, 635( 1-3): 188- 193. DOI: 10.1016/j.ejphar.2010.03.007.
[68]	WANG HJ, CHEN LY, ZHANG XY, et al. Kaempferol protects mice from d-GalN/LPS-induced acute liver failure by regulating the ER stress-Grp78-CHOP signaling pathway[J]. Biomedecine Pharmacother, 2019, 111: 468- 475. DOI: 10.1016/j.biopha.2018.12.105.
[69]	WEN JJ, LIN HF, ZHAO MS, et al. Piceatannol attenuates D-GalN/LPS-induced hepatoxicity in mice: Involvement of ER stress, inflammation and oxidative stress[J]. Int Immunopharmacol, 2018, 64: 131- 139. DOI: 10.1016/j.intimp.2018.08.037.
[70]	LIU H, ZHANG W, DONG SC, et al. Protective effects of sea buckthorn polysaccharide extracts against LPS/d-GalN-induced acute liver failure in mice via suppressing TLR4-NF-κB signaling[J]. J Ethnopharmacol, 2015, 176: 69- 78. DOI: 10.1016/j.jep.2015.10.029.
[71]	TAI MH, ZHANG JY, SONG SD, et al. Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse[J]. Int Immunopharmacol, 2015, 27( 1): 164- 170. DOI: 10.1016/j.intimp.2015.05.009.