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Volume 41 Issue 9
Sep.  2025
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Article Navigation >  Journal of Clinical Hepatology  > 2025  >  41(9): 1943-1948

Mechanisms of aryl hydrocarbon receptor in liver diseases

DOI: 10.12449/JCH250935

  • Department of Radiation Oncology，The First Affiliated Hospital of Guangxi Medical University，Nanning 530021，China

Research funding:

Guangxi Natural Science Foundation-Funded Project (2024GXNSFDA010042)

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  • Corresponding author: HU Kai， hukai@gxmu.edu.cn （ORCID： 0000-0003-4990-0395）
  • Received Date: 2025-01-05
  • Accepted Date: 2025-02-05
  • Published Date: 2025-09-25
    Abstract
  • Aryl hydrocarbon receptor （AhR） plays an important role in the development and progression of liver diseases. This article elaborates on the structure of AhR and its function in liver development and provides a detailed analysis of its molecular mechanisms in diseases such as metabolic associated fatty liver disease， alcoholic liver disease， viral hepatitis， drug-induced liver injury， autoimmune hepatitis， liver cirrhosis， and liver cancer. This article also reviews the research advances in AhR agonists and antagonists and analyzes their potential application prospects in disease treatment. At the same time， it points out that although AhR is a promising therapeutic target， there are still various challenges in its clinical application. It is suggested that future research should focus on developing AhR modulators with high specificity and low toxicity and further explore its mechanism of action in different liver diseases.

     

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  • [1]
    HAHN ME, KARCHNER SI, MERSON RR. Diversity as opportunity: Insights from 600 million years of AHR evolution[J]. Curr Opin Toxicol, 2017, 2: 58- 71. DOI: 10.1016/j.cotox.2017.02.003.
    [2]
    STOCKINGER B, SHAH K, WINCENT E. AHR in the intestinal microenvironment: Safeguarding barrier function[J]. Nat Rev Gastroenterol Hepatol, 2021, 18( 8): 559- 570. DOI: 10.1038/s41575-021-00430-8.
    [3]
    DAI SY, QU LZ, LI J, et al. Structural insight into the ligand binding mechanism of aryl hydrocarbon receptor[J]. Nat Commun, 2022, 13( 1): 6234. DOI: 10.1038/s41467-022-33858-w.
    [4]
    OBER EA, LEMAIGRE FP. Development of the liver: Insights into organ and tissue morphogenesis[J]. J Hepatol, 2018, 68( 5): 1049- 1062. DOI: 10.1016/j.jhep.2018.01.005.
    [5]
    WALISSER JA, GLOVER E, PANDE K, et al. Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types[J]. Proc Natl Acad Sci USA, 2005, 102( 49): 17858- 17863. DOI: 10.1073/pnas.0504757102.
    [6]
    ZHAO Y, BAO RK, ZHU SY, et al. Lycopene prevents DEHP-induced hepatic oxidative stress damage by crosstalk between AHR-Nrf2 pathway[J]. Environ Pollut, 2021, 285: 117080. DOI: 10.1016/j.envpol.2021.117080.
    [7]
    PROCHÁZKOVÁ J, KABÁTKOVÁ M, BRYJA V, et al. The interplay of the aryl hydrocarbon receptor and β-catenin alters both AhR-dependent transcription and Wnt/β-catenin signaling in liver progenitors[J]. Toxicol Sci, 2011, 122( 2): 349- 360. DOI: 10.1093/toxsci/kfr129.
    [8]
    REJANO-GORDILLO CM, GONZÁLEZ-RICO FJ, MARÍN-DÍAZ B, et al. Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor[J]. Sci Rep, 2022, 12( 1): 15446. DOI: 10.1038/s41598-022-19733-0.
    [9]
    ISRAELSEN M, FRANCQUE S, TSOCHATZIS EA, et al. Steatotic liver disease[J]. Lancet, 2024, 404( 10464): 1761- 1778. DOI: 10.1016/S0140-6736(24)01811-7.
    [10]
    KIM YC, SEOK S, BYUN S, et al. AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle[J]. Nat Commun, 2018, 9( 1): 540. DOI: 10.1038/s41467-018-03060-y.
    [11]
    SHIN S, WAKABAYASHI N, MISRA V, et al. NRF2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis[J]. Mol Cell Biol, 2007, 27( 20): 7188- 7197. DOI: 10.1128/MCB.00915-07.
    [12]
    MOYER BJ, ROJAS IY, KERLEY-HAMILTON JS, et al. Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice[J]. Nutr Res, 2017, 44: 38- 50. DOI: 10.1016/j.nutres.2017.06.002.
    [13]
    KANMANI P, VILLENA J, LIM SK, et al. Immunobiotic bacteria attenuate hepatic fibrosis through the modulation of gut microbiota and the activation of aryl-hydrocarbon receptors pathway in non-alcoholic steatohepatitis mice[J]. Mol Nutr Food Res, 2024, 68( 14): e2400227. DOI: 10.1002/mnfr.202400227.
    [14]
    DONG HB, HAO LY, ZHANG WL, et al. Activation of AhR-NQO1 signaling pathway protects against alcohol-induced liver injury by improving redox balance[J]. Cell Mol Gastroenterol Hepatol, 2021, 12( 3): 793- 811. DOI: 10.1016/j.jcmgh.2021.05.013.
    [15]
    WRZOSEK L, CIOCAN D, HUGOT C, et al. Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury[J]. Gut, 2021, 70( 7): 1299- 1308. DOI: 10.1136/gutjnl-2020-321565.
    [16]
    ODENWALD MA, PAUL S. Viral hepatitis: Past, present, and future[J]. World J Gastroenterol, 2022, 28( 14): 1405- 1429. DOI: 10.3748/wjg.v28.i14.1405.
    [17]
    ZHANG RY, LIU HE, LIN J, et al. AhR may be involved in Th17 cell differentiation in chronic hepatitis B[J]. J Viral Hepat, 2023, 30( 12): 939- 950. DOI: 10.1111/jvh.13883.
    [18]
    FURUTANI Y, HIRANO Y, TOGUCHI M, et al. A small molecule iCDM-34 identified by in silico screening suppresses HBV DNA through activation of aryl hydrocarbon receptor[J]. Cell Death Discov, 2023, 9( 1): 467. DOI: 10.1038/s41420-023-01755-w.
    [19]
    OHASHI H, NISHIOKA K, NAKAJIMA S, et al. The aryl hydrocarbon receptor-cytochrome P450 1A1 pathway controls lipid accumulation and enhances the permissiveness for hepatitis C virus assembly[J]. J Biol Chem, 2018, 293( 51): 19559- 19571. DOI: 10.1074/jbc.RA118.005033.
    [20]
    NAKAMURA K, YAMASAKI M, OHASHI H, et al. Identification of methylsulochrin as a partial agonist for aryl hydrocarbon receptors and its antiviral and anti-inflammatory activities[J]. Chem Pharm Bull(Tokyo), 2023, 71( 8): 650- 654. DOI: 10.1248/cpb.c23-00243.
    [21]
    BJÖRNSSON HK, BJÖRNSSON ES. Drug-induced liver injury: Pathogenesis, epidemiology, clinical features, and practical management[J]. Eur J Intern Med, 2022, 97: 26- 31. DOI: 10.1016/j.ejim.2021.10.035.
    [22]
    PAPAGEORGIOU I, FREYTSIS M, COURT MH. Transcriptome association analysis identifies miR-375 as a major determinant of variable acetaminophen glucuronidation by human liver[J]. Biochem Pharmacol, 2016, 117: 78- 87. DOI: 10.1016/j.bcp.2016.08.014.
    [23]
    SCHURAN FA, LOMMETZ C, STEUDTER A, et al. Aryl hydrocarbon receptor activity in hepatocytes sensitizes to hyperacute acetaminophen-induced hepatotoxicity in mice[J]. Cell Mol Gastroenterol Hepatol, 2021, 11( 2): 371- 388. DOI: 10.1016/j.jcmgh.2020.09.002.
    [24]
    WANG MX, ZHANG ZQ, RUAN PP, et al. Emodin-induced hepatotoxicity is enhanced by 3-methylcholanthrene through activating aryl hydrocarbon receptor and inducing CYP1A1 in vitro and in vivo[J]. Chem Biol Interact, 2022, 365: 110089. DOI: 10.1016/j.cbi.2022.110089.
    [25]
    ZHANG Y, LE Y, JI Y, et al. Activation of activator protein-1-fibroblast growth factor 21 signaling attenuates Cisplatin hepatotoxicity[J]. Biochem Pharmacol, 2021, 194: 114823. DOI: 10.1016/j.bcp.2021.114823.
    [26]
    MURATORI L, LOHSE AW, LENZI M. Diagnosis and management of autoimmune hepatitis[J]. BMJ, 2023, 380: e070201. DOI: 10.1136/bmj-2022-070201.
    [27]
    VUERICH M, HARSHE R, FRANK LA, et al. Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis[J]. J Hepatol, 2021, 74( 1): 48- 57. DOI: 10.1016/j.jhep.2020.06.044.
    [28]
    CANNON AS, HOLLOMAN BL, WILSON K, et al. 6-Formylindolo[3, 2-b] carbazole, a potent ligand for the aryl hydrocarbon receptor, attenuates concanavalin-induced hepatitis by limiting T-cell activation and infiltration of proinflammatory CD11b+ Kupffer cells[J]. J Leukoc Biol, 2024, 115( 6): 1070- 1083. DOI: 10.1093/jleuko/qiae018.
    [29]
    PANDEY SP, BENDER MJ, MCPHERSON AC, et al. Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis[J]. Cell Host Microbe, 2022, 30( 7): 1003- 1019. DOI: 10.1016/j.chom.2022.05.006.
    [30]
    GINÈS P, KRAG A, ABRALDES JG, et al. Liver cirrhosis[J]. Lancet, 2021, 398( 10308): 1359- 1376. DOI: 10.1016/S0140-6736(21)01374-X.
    [31]
    YANG CG, WANG YN, HUA MR, et al. Aryl hydrocarbon receptor: From pathogenesis to therapeutic targets in aging-related tissue fibrosis[J]. Ageing Res Rev, 2022, 79: 101662. DOI: 10.1016/j.arr.2022.101662.
    [32]
    ANDREOLA F, CALVISI DF, ELIZONDO G, et al. Reversal of liver fibrosis in aryl hydrocarbon receptor null mice by dietary vitamin A depletion[J]. Hepatology, 2004, 39( 1): 157- 166. DOI: 10.1002/hep.20004.
    [33]
    WANG Y, DENG BC. Hepatocellular carcinoma: Molecular mechanism, targeted therapy, and biomarkers[J]. Cancer Metastasis Rev, 2023, 42( 3): 629- 652. DOI: 10.1007/s10555-023-10084-4.
    [34]
    ZHU Q, MA YR, LIANG JB, et al. AHR mediates the aflatoxin B1 toxicity associated with hepatocellular carcinoma[J]. Signal Transduct Target Ther, 2021, 6( 1): 299. DOI: 10.1038/s41392-021-00713-1.
    [35]
    CHEN CT, WU PH, HU CC, et al. Aberrant upregulation of indoleamine 2, 3-dioxygenase 1 promotes proliferation and metastasis of hepatocellular carcinoma cells via coordinated activation of AhR and β-catenin signaling[J]. Int J Mol Sci, 2021, 22( 21): 11661. DOI: 10.3390/ijms222111661.
    [36]
    MORENO-MARÍN N, BARRASA E, MORALES-HERNÁNDEZ A, et al. Dioxin receptor adjusts liver regeneration after acute toxic injury and protects against liver carcinogenesis[J]. Sci Rep, 2017, 7( 1): 10420. DOI: 10.1038/s41598-017-10984-w.
    [37]
    PAN PH, WANG YY, LIN SY, et al. Plumbagin ameliorates bile duct ligation-induced cholestatic liver injury in rats[J]. Biomed Pharmacother, 2022, 151: 113133. DOI: 10.1016/j.biopha.2022.113133.
    [38]
    LI TT, XU LJ, ZHENG RY, et al. Picroside II protects against cholestatic liver injury possibly through activation of farnesoid X receptor[J]. Phytomedicine, 2020, 68: 153153. DOI: 10.1016/j.phymed.2019.153153.
    [39]
    SHIN HS, LEE HJ, PYO MC, et al. Ochratoxin A-induced hepatotoxicity through phase I and phase II reactions regulated by AhR in liver cells[J]. Toxins(Basel), 2019, 11( 7): 377. DOI: 10.3390/toxins11070377.
    [40]
    DENISON MS, NAGY SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals[J]. Annu Rev Pharmacol Toxicol, 2003, 43: 309- 334. DOI: 10.1146/annurev.pharmtox.43.100901.135828.
    [41]
    LAMAS B, RICHARD ML, LEDUCQ V, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands[J]. Nat Med, 2016, 22( 6): 598- 605. DOI: 10.1038/nm.4102.
    [42]
    TSUJI G, YUMINE A, KAWAMURA K, et al. Induction of semaphorin 3A by resveratrol and pinostilbene via activation of the AHR-NRF2 axis in human keratinocytes[J]. Antioxidants(Basel), 2024, 13( 6): 732. DOI: 10.3390/antiox13060732.
    [43]
    BONATI L, CORRADA D, TAGLIABUE SG, et al. Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms[J]. Curr Opin Toxicol, 2017, 2: 42- 49. DOI: 10.1016/j.cotox.2017.01.011.
    [44]
    TRIKHA P, LEE DA. The role of AhR in transcriptional regulation of immune cell development and function[J]. Biochim Biophys Acta Rev Cancer, 2020, 1873( 1): 188335. DOI: 10.1016/j.bbcan.2019.188335.
    [45]
    HAN L, MA CH, WU ZT, et al. AhR-STAT3-HO-1/COX-2 signalling pathway may restrict ferroptosis and improve hMSC accumulation and efficacy in mouse liver[J]. Br J Pharmacol, 2024, 181( 1): 125- 141. DOI: 10.1111/bph.16208.
    [46]
    ZHAO TT, LI JF, ZHANG LT. Progress in the potential therapeutic mechanism of mesenchymal stem cell-derived exosomes for liver fibrosis[J]. Chin J Clin Pharmacol Ther, 2024, 29( 4): 475- 480. DOI: 10.12092/j.issn.1009-2501.2024.04.017.

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