整合素在肝纤维化中的作用：从机制到治疗

宋玉芸; 殷珂; 刘峰

doi:10.12449/JCH251227

整合素在肝纤维化中的作用：从机制到治疗

DOI: 10.12449/JCH251227

北京大学人民医院，北京大学肝病研究所，北京大学人民医院感染与肝病中心，北京 100044

基金项目:

国家自然科学基金 (82170584);

北京市自然科学基金 (7242151);

其敏计划 (202308)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：宋玉芸、殷珂负责文献检索，撰写文章；刘峰负责修改和审校文章。

详细信息

通信作者:
刘峰， liu1116m@sina.com（ORCID： 0000-0002-0316-4938）

计量
- 文章访问数: 5
- HTML全文浏览量: 3
- PDF下载量: 4
- 被引次数: 0
出版历程
- 收稿日期: 2025-05-06
- 录用日期: 2025-09-09
- 出版日期: 2025-12-25

Role of integrins in liver fibrosis： From mechanism to treatment

Peking University People’s Hospital，Peking University Hepatology Institute，Infectious Disease and Hepatology Center of Peking University People’s Hospital，Beijing 100044，China

Research funding:

National Natural Science Foundation of China (82170584);

Beijing Natural Science Foundation (7242151);

Qimin Plan (202308)

More Information

Corresponding author: LIU Feng， liu1116m@sina.com （ORCID： 0000-0002-0316-4938）

摘要

摘要: 肝纤维化是慢性肝病发展至肝硬化的关键阶段，以细胞外基质（ECM）过度沉积为主要特征。整合素（包含α和β亚基）作为细胞与ECM相互作用的关键分子，参与细胞黏附、信号传导和细胞迁移等过程，在肝纤维化中发挥重要作用。在肝纤维化进程中，整合素的表达上调，通过与ECM的相互作用促进肝星状细胞的活化和增殖，加速ECM的合成和沉积。其中，整合素αVβ3和αVβ6在肝纤维化中的表达增加尤为显著，与TGF-β信号通路的激活密切相关。此外，整合素还与炎症反应和肝脏再生修复过程相关。整合素作为治疗靶点具有巨大潜力，针对整合素的抑制剂有望为肝纤维化提供新的治疗策略。
- 肝纤维化 /
- 整合素类 /
- 肝星状细胞 /
- 治疗学
Abstract: Liver fibrosis is a key pathological stage in the progression of chronic liver diseases to liver cirrhosis and is characterized by excessive extracellular matrix （ECM） deposition. As critical mediators of cell-ECM crosstalk， integrins play an important role in the development and progression of liver fibrosis. The integrin family includes α and β subunits and is widely involved in the regulation of cell adhesion， migration， and signal transduction. In the process of liver fibrosis， the expression of integrins is upregulated， and its interaction with ECM promotes the activation and proliferation of hepatic stellate cells， further accelerating the synthesis and deposition of ECM. The increases in the expression of integrins αVβ3 and αVβ6 are closely associated with the activation of the TGF-β signaling pathway. In addition， integrins also modulate inflammatory responses and tissue regeneration and repair in the liver. Based on the above mechanisms， integrins have become the potential targets for the treatment of liver fibrosis， and inhibitors targeting integrins may become a new strategy for the treatment of liver fibrosis.
- Liver Fibrosis /
- Integrins /
- Hepatic Stellate Cells /
- Therapeutics

HTML全文

表 1 肝纤维化治疗中整合素相关靶点药物

Table 1. Integrin-related target drugs in the treatment of liver fibrosis

药物	靶点	机制	临床试验阶段
Abituzumab^［38-42］	整合素αV	拮抗整合素αV	未开展
intetumumab^［38-42］	整合素αV	拮抗整合素αV	未开展
cilengitide^［38-42］	整合素αV	拮抗整合素αV	未开展
BG00011^［38-42］	整合素αV	拮抗整合素αV	未开展
MK-0429^［38-42］	整合素αV	拮抗整合素αV	未开展
CWHM-12^［43］	整合素αV	拮抗整合素αV	肝硬化临床前
PLN-1474^［45］	整合素αVβ1	拮抗整合素αV和整合素β1	非酒精性脂肪性肝炎和肝硬化临床Ⅰ期
PLN-74809^［44］	整合素αVβ1；整合素αVβ6	拮抗整合素αV和整合素β1；拮抗整合素αV和整合素β6	硬化性胆管炎临床 Ⅱ期
cRGDyK^［46］	整合素αVβ3	基于整合素αVβ3的纳米粒子cRGDyK引导的脂质小体靶向活化的HSC并缓解肝纤维化	未开展
miR-190b-5p^［47］	整合素α6	靶向透明质合酶2和整合素α6治疗肝纤维化	未开展
miR-296-3p^［47］	整合素α6	靶向透明质合酶2和整合素α6治疗肝纤维化	未开展
扶正化瘀方^［48-49］	整合素α5β1	拮抗整合素α5和整合素β1；抑制纤维连接蛋白刺激的HSC增殖活化，下调整合素/ FAK信号通路	未开展
肝复康^［50］	整合素α5β1	抑制整合素α5β1/FAK通路	未开展
灵芝多糖^［51］	整合素α6；整合素α8	减少整合素α6和整合素α8表达，通过TLR4/NF-κB/ MyD88信号通路抑制肝纤维化和炎症	未开展
XHH2^［52］	整合素β1	干扰Gal-3/整合素β1/FAK通路失活HSC，减轻肝损伤和肝纤维化	未开展
蒙古山萝卜花总黄酮提取物^［53］	整合素β4	抑制整合素β4/FAK/p38通路，抑制HSC-T6细胞活化、增殖，促进凋亡	未开展

下载: 导出CSV

参考文献(53)

[1]	Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Gastroenterology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Consensus on the diagnosis and therapy of hepatic fibrosis(2019)[J]. J Clin Hepatol, 2019, 35( 10): 2163- 2172. DOI: 10.3969/j.issn.1001-5256.2019.10.007. 中华医学会肝病学分会, 中华医学会消化病学分会, 中华医学会感染病学分会. 肝纤维化诊断及治疗共识(2019年)[J]. 临床肝胆病杂志, 2019, 35( 10): 2163- 2172. DOI: 10.3969/j.issn.1001-5256.2019.10.007.
[2]	HSU YC, HUANG DQ, NGUYEN MH. Global burden of hepatitis B virus: Current status, missed opportunities and a call for action[J]. Nat Rev Gastroenterol Hepatol, 2023, 20( 8): 524- 537. DOI: 10.1038/s41575-023-00760-9.
[3]	YOUNOSSI ZM, GOLABI P, PAIK JM, et al. The global epidemiology of nonalcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis(NASH): A systematic review[J]. Hepatology, 2023, 77( 4): 1335- 1347. DOI: 10.1097/HEP.0000000000000004.
[4]	HUANG DQ, TERRAULT NA, TACKE F, et al. Global epidemiology of cirrhosis: Aetiology, trends and predictions[J]. Nat Rev Gastroenterol Hepatol, 2023, 20( 6): 388- 398. DOI: 10.1038/s41575-023-00759-2.
[5]	TSUCHIDA T, FRIEDMAN SL. Mechanisms of hepatic stellate cell activation[J]. Nat Rev Gastroenterol Hepatol, 2017, 14( 7): 397- 411. DOI: 10.1038/nrgastro.2017.38.
[6]	LI RS, FRANGOGIANNIS NG. Integrins in cardiac fibrosis[J]. J Mol Cell Cardiol, 2022, 172: 1- 13. DOI: 10.1016/j.yjmcc.2022.07.006.
[7]	LI ZH, ZHOU Y, DING YX, et al. Roles of integrin in tumor development and the target inhibitors[J]. Chin J Nat Med, 2019, 17( 4): 241- 251. DOI: 10.1016/S1875-5364(19)30028-7.
[8]	MASUZAKI R, RAY KC, ROLAND J, et al. Integrin β1 establishes liver microstructure and modulates transforming growth factor β during liver development and regeneration[J]. Am J Pathol, 2021, 191( 2): 309- 319. DOI: 10.1016/j.ajpath.2020.10.011.
[9]	LORENZ L, AXNICK J, BUSCHMANN T, et al. Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival[J]. Nature, 2018, 562( 7725): 128- 132. DOI: 10.1038/s41586-018-0522-3.
[10]	PENG Z, HAO M, TONG HB, et al. The interactions between integrin α₅β₁ of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis[J]. Int J Biol Sci, 2022, 18( 13): 5019- 5037. DOI: 10.7150/ijbs.72367.
[11]	SUN FK, WANG JP, SUN Q, et al. Interleukin-8 promotes integrin β3 upregulation and cell invasion through PI3K/Akt pathway in hepatocellular carcinoma[J]. J Exp Clin Cancer Res, 2019, 38( 1): 449. DOI: 10.1186/s13046-019-1455-x.
[12]	YAN YX, MA YH, LIANG J, et al. Research progress of integrin pathway involved in organ fibrosis[J]. J Dis Monit Control, 2019, 13( 4): 320- 322. 颜羽昕, 马月宏, 梁洁, 等. 整合素通路参与器官纤维化过程的研究进展[J]. 疾病监测与控制, 2019, 13( 4): 320- 322.
[13]	HE ZB, NIU WB, PENG C, et al. The relationship between integrin avß6 and HBV infection in patients with liver cirrhosis and hepatocellular carcinoma: A preliminary report[J]. Rev Esp Enferm Dig, 2020, 112( 6): 462- 466. DOI: 10.17235/reed.2020.6607/2019.
[14]	NATARAJ K, SCHONFELD M, RODRIGUEZ A, et al. Protective role of 17β-estradiol in alcohol-associated liver fibrosis is mediated by suppression of integrin signaling[J]. Hepatol Commun, 2024, 8( 5): e0428. DOI: 10.1097/HC9.0000000000000428.
[15]	SUN CB, FAN WG, BASHA S, et al. Extracellular matrix protein 1 binds to connective tissue growth factor against liver fibrosis and ductular reaction[J]. Hepatol Commun, 2024, 8( 11): e0564. DOI: 10.1097/HC9.0000000000000564.
[16]	KANAAN R, MEDLEJ-HASHIM M, JOUNBLAT R, et al. Microfibrillar-associated protein 4 in health and disease[J]. Matrix Biol, 2022, 111: 1- 25. DOI: 10.1016/j.matbio.2022.05.008.
[17]	KIM DH, SUNG M, PARK MS, et al. Galectin 3-binding protein(LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor-β1(TGF-β1) availability and inhibits hepatocarcinogenesis[J]. Cancer Commun, 2024, 44( 10): 1106- 1129. DOI: 10.1002/cac2.12600.
[18]	LIANG JJ, MA L, WU JF. Reseach progress on the role of integrins and related miRNAs in liver fibrosis[J]. Chin J Anat, 2021, 44( 2): 152- 155. DOI: 10.3969/j.issn.1001-1633.2021.02.012. 梁家杰, 马岚, 吴江锋. 整合素及其相关miRNA在肝纤维化中作用的研究进展[J]. 解剖学杂志, 2021, 44( 2): 152- 155. DOI: 10.3969/j.issn.1001-1633.2021.02.012.
[19]	SHEPPARD D. Epithelial-mesenchymal interactions in fibrosis and repair. Transforming growth factor-β activation by epithelial cells and fibroblasts[J]. Ann Am Thorac Soc, 2015, 12( Suppl 1): S21- S23. DOI: 10.1513/AnnalsATS.201406-245MG.
[20]	ZHONG L, ZHAO JQ, HUANG L, et al. Runx2 activates hepatic stellate cells to promote liver fibrosis via transcriptionally regulating Itgav expression[J]. Clin Transl Med, 2023, 13( 7): e1316. DOI: 10.1002/ctm2.1316.
[21]	ZUO T, XIE Q, LIU JF, et al. Macrophage-derived cathepsin S remodels the extracellular matrix to promote liver fibrogenesis[J]. Gastroenterology, 2023, 165( 3): 746- 761.e16. DOI: 10.1053/j.gastro.2023.05.039.
[22]	DU ZP, LIN ZY, WANG ZH, et al. SPOCK1 overexpression induced by platelet-derived growth factor-BB promotes hepatic stellate cell activation and liver fibrosis through the integrin α5β1/PI3K/Akt signaling pathway[J]. Lab Invest, 2020, 100( 8): 1042- 1056. DOI: 10.1038/s41374-020-0425-4.
[23]	CAI QX, CHEN FJ, XU F, et al. Epigenetic silencing of microRNA-125b-5p promotes liver fibrosis in nonalcoholic fatty liver disease via integrin α8-mediated activation of RhoA signaling pathway[J]. Metabolism, 2020, 104: 154140. DOI: 10.1016/j.metabol.2020.154140.
[24]	YANG AT, YAN XZ, XU HF, et al. Selective depletion of hepatic stellate cells-specific LOXL1 alleviates liver fibrosis[J]. FASEB J, 2021, 35( 10): e21918. DOI: 10.1096/fj.202100374R.
[25]	NISHIMICHI N, TSUJINO K, KANNO K, et al. Induced hepatic stellate cell integrin, α8β1, enhances cellular contractility and TGFβ activity in liver fibrosis[J]. J Pathol, 2021, 253( 4): 366- 373. DOI: 10.1002/path.5618.
[26]	KUMAZOE M, MIYAMOTO E, OKA C, et al. miR-12135 ameliorates liver fibrosis accompanied with the downregulation of integrin subunit alpha 11[J]. iScience, 2024, 27( 1): 108730. DOI: 10.1016/j.isci.2023.108730.
[27]	RAI RP, LIU YS, IYER SS, et al. Blocking integrin α₄β₇-mediated CD4 T cell recruitment to the intestine and liver protects mice from western diet-induced non-alcoholic steatohepatitis[J]. J Hepatol, 2020, 73( 5): 1013- 1022. DOI: 10.1016/j.jhep.2020.05.047.
[28]	SCHONFELD M, VILLAR MT, ARTIGUES A, et al. Arginine methylation of integrin alpha-4 prevents fibrosis development in alcohol-associated liver disease[J]. Cell Mol Gastroenterol Hepatol, 2023, 15( 1): 39- 59. DOI: 10.1016/j.jcmgh.2022.09.013.
[29]	KIM KH, CHENG NY, LAU LF. Cellular communication network factor 1-stimulated liver macrophage efferocytosis drives hepatic stellate cell activation and liver fibrosis[J]. Hepatol Commun, 2022, 6( 10): 2798- 2811. DOI: 10.1002/hep4.2057.
[30]	SUN ZQ, CERNILOGAR FM, HORVATIC H, et al. β1 integrin signaling governs necroptosis via the chromatin-remodeling factor CHD4[J]. Cell Rep, 2023, 42( 11): 113322. DOI: 10.1016/j.celrep.2023.113322.
[31]	XU T, LU ZW, XIAO ZL, et al. Myofibroblast induces hepatocyte-to-ductal Metaplasia via laminin-αvβ6 integrin in liver fibrosis[J]. Cell Death Dis, 2020, 11( 3): 199. DOI: 10.1038/s41419-020-2372-9.
[32]	POZNIAK KN, PEAREN MA, PEREIRA TN, et al. Taurocholate induces biliary differentiation of liver progenitor cells causing hepatic stellate cell chemotaxis in the ductular reaction: Role in pediatric cystic fibrosis liver disease[J]. Am J Pathol, 2017, 187( 12): 2744- 2757. DOI: 10.1016/j.ajpath.2017.08.024.
[33]	HU QH, SU YZ, MA SY, et al. Integrin-targeted theranostic nanoparticles for clinical MRI-traceable treatment of liver fibrosis[J]. ACS Appl Mater Interfaces, 2024, 16( 2): 2012- 2026. DOI: 10.1021/acsami.3c12776.
[34]	TANG XY, LI X, LI MX, et al. Enhanced US/CT/MR imaging of integrin α_vβ₃ for liver fibrosis staging in rat[J]. Front Chem, 2022, 10: 996116. DOI: 10.3389/fchem.2022.996116.
[35]	SHAO T, CHEN Z, BELOV V, et al.[¹⁸F]-Alfatide PET imaging of integrin αvβ3 for the non-invasive quantification of liver fibrosis[J]. J Hepatol, 2020, 73( 1): 161- 169. DOI: 10.1016/j.jhep.2020.02.018.
[36]	YU X, WU Y, LIU H, et al. Small-animal SPECT/CT of the progression and recovery of rat liver fibrosis by using an integrin α_vβ₃-targeting radiotracer[J]. Radiology, 2016, 279( 2): 502- 512. DOI: 10.1148/radiol.2015150090.
[37]	ZHANG X, GUO QY, SHI Y, et al. ^99mTc-3PRGD2 scintigraphy to stage liver fibrosis and evaluate reversal after fibrotic stimulus withdrawn[J]. Nucl Med Biol, 2017, 49: 44- 49. DOI: 10.1016/j.nucmedbio.2017.02.004.
[38]	O'DAY S, PAVLICK A, LOQUAI C, et al. A randomised, phase II study of intetumumab, an anti-αv-integrin MAb, alone and with dacarbazine in stage IV melanoma[J]. Br J Cancer, 2011, 105( 3): 346- 352. DOI: 10.1038/bjc.2011.183.
[39]	DESGROSELLIER JS, CHERESH DA. Integrins in cancer: Biological implications and therapeutic opportunities[J]. Nat Rev Cancer, 2010, 10( 1): 9- 22. DOI: 10.1038/nrc2748.
[40]	RAGHU G, MOUDED M, CHAMBERS DC, et al. A phase IIb randomized clinical study of an anti-α_vβ₆ monoclonal antibody in idiopathic pulmonary fibrosis[J]. Am J Respir Crit Care Med, 2022, 206( 9): 1128- 1139. DOI: 10.1164/rccm.202112-2824OC.
[41]	ZHANG H, WANG ZL, NGUYEN HTT, et al. Integrin α₅β₁ contributes to cell fusion and inflammation mediated by SARS-CoV-2 spike via RGD-independent interaction[J]. Proc Natl Acad Sci USA, 2023, 120( 50): e2311913120. DOI: 10.1073/pnas.2311913120.
[42]	ÉLEZ E, KOCÁKOVÁ I, HÖHLER T, et al. Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: The randomised phase I/II POSEIDON trial[J]. Ann Oncol, 2015, 26( 1): 132- 140. DOI: 10.1093/annonc/mdu474.
[43]	HENDERSON NC, ARNOLD TD, KATAMURA Y, et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs[J]. Nat Med, 2013, 19( 12): 1617- 1624. DOI: 10.1038/nm.3282.
[44]	RAHMAN SR, ROPER JA, GROVE JI, et al. Integrins as a drug target in liver fibrosis[J]. Liver Int, 2022, 42( 3): 507- 521. DOI: 10.1111/liv.15157.
[45]	NOVARTIS AG PLIANT THERAPEUTICS, INC. Combination treatment of liver diseases using integrin inhibitors: 20230060422[P]. 2023-03-02.
[46]	LI YP, PU SY, LIU QH, et al. An integrin-based nanoparticle that targets activated hepatic stellate cells and alleviates liver fibrosis[J]. J Control Release, 2019, 303: 77- 90. DOI: 10.1016/j.jconrel.2019.04.022.
[47]	MARKOVIC J, LI RM, KHANAL R, et al. Identification and functional validation of miR-190b-5p and miR-296-3p as novel therapeutic attenuators of liver fibrosis[J]. J Hepatol, 2025, 82( 2): 301- 314. DOI: 10.1016/j.jhep.2024.08.014.
[48]	XUAN HP, SUN BM, TAO YY, et al. Dynamic changes of integrin α5β1 in the development of liver fibrosis and the effects of Fuzheng Huayu decoction[J]. Chin Hepatol, 2004, 9( 3): 163- 166. DOI: 10.3969/j.issn.1008-1704.2004.03.006. 宣红萍, 孙保木, 陶艳艳, 等. 肝纤维化过程中整合素α5β1动态变化与扶正化瘀方干预作用[J]. 肝脏, 2004, 9( 3): 163- 166. DOI: 10.3969/j.issn.1008-1704.2004.03.006.
[49]	LIU CH, XUAN HP, TAO YY, et al. Mechanism of"fuzheng Huayu recipe" against hepatic stellate cell activation through FN/integrin signaling[J]. Shanghai J Tradit Chin Med, 2008, 42( 1): 3- 7. DOI: 10.16305/j.1007-1334.2008.01.028. 刘成海, 宣红萍, 陶艳艳, 等. 基于FN/整合素信号途径探讨扶正化瘀方抑制肝星状细胞活化的作用机制[J]. 上海中医药杂志, 2008, 42( 1): 3- 7. DOI: 10.16305/j.1007-1334.2008.01.028.
[50]	ZHANG K, JIANG MN, ZHANG CH, et al. Effect of Gan-fu-Kang compound on hepatic expression of integrin α5β1/FAK signal pathway in carbon tetrachloride-induced liver fibrosis in rats[J]. J Clin Hepatol, 2012, 15( 2): 104- 107. DOI: 10.3969/j.issn.1672-5069.2012.02.008. 张坤, 姜妙娜, 张彩华, 等. 肝复康对肝纤维化大鼠肝组织整合素α5β1/FAK信号通路的调节作用[J]. 实用肝脏病杂志, 2012, 15( 2): 104- 107. DOI: 10.3969/j.issn.1672-5069.2012.02.008.
[51]	CHEN CJ, CHEN JJ, WANG Y, et al. Ganoderma lucidum polysaccharide inhibits HSC activation and liver fibrosis via targeting inflammation, apoptosis, cell cycle, and ECM-receptor interaction mediated by TGF-β/Smad signaling[J]. Phytomedicine, 2023, 110: 154626. DOI: 10.1016/j.phymed.2022.154626.
[52]	TANG BX, JIN C, LI MT, et al. A novel pectin-like polysaccharide from Crocus sativus targets Galectin-3 to inhibit hepatic stellate cells activation and liver fibrosis[J]. Carbohydr Polym, 2025, 348( Pt A): 122826. DOI: 10.1016/j.carbpol.2024.122826.
[53]	MENG GSLM. Anti-liver fibrosis effect of total flavonoid extract from Scabiosa comosa Fisch. ex Roem. et Schult and its effect on ITGB4/FAK/p38 pathway[D]. Hohhot: Inner Mongolia Medical University, 2020. 孟根斯立木. 蒙古山萝卜花总黄酮提取物抗肝纤维化作用及对ITGB4/FAK/p38通路的影响[D]. 呼和浩特: 内蒙古医科大学, 2020.