中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 41 Issue 12
Dec.  2025
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2025  >  41(12): 2636-2642

Role of integrins in liver fibrosis： From mechanism to treatment

DOI: 10.12449/JCH251227

  • 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）
  • Received Date: 2025-05-06
  • Accepted Date: 2025-09-09
  • Published Date: 2025-12-25
    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.

     

    • FullText(HTML)
  • loading
    • References(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 αvβ3 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 αvβ3-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-αvβ6 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.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Tables(1)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (44) PDF downloads(18) Cited by()
    Proportional views
    Related
        

    The first journal specializing in hepatobiliary and pancreatic diseases in China

    Supervisor：Ministry of Education of the People's Republic of China

    Sponsor：Jilin University

    Academic Support: Chinese Society of Hepatology，Chinese Medical Association

    Address: 461 Xinjiang Road, Changchun

    Submit：0431-88782044

    Peer review：0431-88783542

    Email：lcgdb@vip.163.com

    About Journal

    Submission Guideline

    Journal Online

    Hepatobiliary College

    Guidelines

    YesterdayIP[]YesterdayPV[]TodayIP[]TodayPV[]Online[]

    Website Design © 2020 Editorial Board of Journal of Clinical Hepatology 吉ICP备10000617号-1 Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return