CoChat
Sign Up
Cited by 837Liver physiology and pathologyTGF-β signaling in diseasesLiver Disease Diagnosis and Treatment

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Open access
Dewidar, Bedair, Meyer, Christoph, Dooley, Steven, Meindl-Beinker, and Nadja·2019·Cells
DOI 10.3390/cells8111419PMC PMC6912224
Open this paper in CoChat — free accountOpen PDF

Abstract

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/cells8111419

Cites

16 of 16 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Tregs can paradoxically promote HSC activation through TGF-β-dependent signaling and IL-8 induction, facilitating fibrogenesis.

    “While Tregs secrete anti-inflammatory cytokines like IL-10, IL-35, and TGF-β (Dikiy and Rudensky 2023), they can paradoxically promote HSC activation through TGF-β-dependent signaling pathway and IL-8 induction, thereby facilitating fibrogenesis (Dewidar et al. 2019; Langhans et al. 2013; Zhu et al. 2015).”

    From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Dewidar et al. 2019

    Section 1.1 states that TGF-β signaling drives HSC activation and fibrogenesis. But the paper does not establish that Tregs cause this activation or induce IL-8; Section 10 instead describes Tregs as mediating an anti-inflammatory effect of TGF-β, distinct from its profibrogenic effects. The claim’s Treg-specific mechanism is therefore unsupported by this source. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • TGF-β, despite immunoregulatory functions, is a potent pro-fibrotic cytokine in liver disease; under sustained injury, it promotes HSC activation and transdifferentiation into ECM-producing myofibroblasts.

    “Notably, TGF-β, despite its immunoregulatory functions, is also a potent pro-fibrotic cytokine in liver disease; under conditions of sustained hepatic injury, TGF-β promotes HSC activation and their transdifferentiation into ECM-producing myofibroblasts, thus driving fibrogenic progression (Dewidar et al. 2019; Tsuchida and Friedman 2017).”

    From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Dewidar et al. 2019

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 263

  1. [1]Chen J.Y. Thakar D. Chang T.T. Liver Fibrosis: Current Approaches and Future Directions for Diagnosis and Treatment Fibrosis in Disease: An Organ-Based Guide to Disease Pathophysiology and Therapeutic Considerations Willis M.S. Yates C.C. Schisler J.C. Springer Cham, Germany 2019 387 417
  2. [2]Hernandez-Gea V. Friedman S.L. Pathogenesis of liver fibrosis Annu. Rev. Pathol. 2011 6 425 456 10.1146/annurev-pathol-011110-130246 21073339 · DOI · Paper page
  3. [3]Ni Y. Li J.-M. Liu M.-K. Zhang T.-T. Wang D.-P. Zhou W.-H. Hu L.-Z. Lv W.-L. Pathological process of liver sinusoidal endothelial cells in liver diseases World J. Gastroenterol. 2017 23 7666 7677 10.3748/wjg.v23.i43.7666 29209108 PMC5703927 · DOI
  4. [4]Elpek G.Ö. Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update World J. Gastroenterol. 2014 20 7260 7276 10.3748/wjg.v20.i23.7260 24966597 PMC4064072 · DOI
  5. [5]Seki E. Brenner D.A. Recent advancement of molecular mechanisms of liver fibrosis J. Hepato-Biliary-Pancreat. Sci. 2015 22 512 518 10.1002/jhbp.245 25869468 PMC4668270 · DOI
  6. [6]Pellicoro A. Ramachandran P. Iredale J.P. Fallowfield J.A. Liver fibrosis and repair: Immune regulation of wound healing in a solid organ Nat. Rev. Immunol. 2014 14 181 194 10.1038/nri3623 24566915 · DOI · Paper page
  7. [7]Zhao Y.-L. Zhu R.-T. Sun Y.-L. Epithelial-mesenchymal transition in liver fibrosis Biomed. Rep. 2016 4 269 274 10.3892/br.2016.578 26998262 PMC4774315 · DOI
  8. [8]Fabregat I. Caballero-Díaz D. Transforming growth factor-β-induced cell plasticity in liver fibrosis and hepatocarcinogenesis Front. Oncol. 2018 8 357 10.3389/fonc.2018.00357 30250825 PMC6139328 · DOI
  9. [9]Tsuchida T. Friedman S.L. Mechanisms of hepatic stellate cell activation Nat. Rev. Gastroenterol. Hepatol. 2017 14 397 411 10.1038/nrgastro.2017.38 28487545 · DOI · Paper page
  10. [10]Dewidar B. Soukupova J. Fabregat I. Dooley S. TGF-β in hepatic stellate cell activation and liver fibrogenesis: Updated Curr. Pathobiol. Rep. 2015 3 291 305 10.1007/s40139-015-0089-8 · DOI
  11. [11]Schon H.-T. Weiskirchen R. Immunomodulatory effects of transforming growth factor-β in the liver Hepatobiliary Surg. Nutr. 2014 3 386 406 25568862 PMC4273109
  12. [12]Ghafoory S. Varshney R. Robison T. Kouzbari K. Woolington S. Murphy B. Xia L. Ahamed J. Platelet TGF-β1 deficiency decreases liver fibrosis in a mouse model of liver injury Blood Adv. 2018 2 470 480 10.1182/bloodadvances.2017010868 29490978 PMC5851416 · DOI
  13. [14]Dickson M.C. Martin J.S. Cousins F.M. Kulkarni A.B. Karlsson S. Akhurst R.J. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice Development 1995 121 1845 1854 7600998
  14. [15]Kaartinen V. Voncken J.W. Shuler C. Warburton D. Bu D. Heisterkamp N. Groffen J. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction Nat. Genet. 1995 11 415 421 10.1038/ng1295-415 7493022 · DOI
  15. [16]Sanford L.P. Ormsby I. Gittenberger-de Groot A.C. Sariola H. Friedman R. Boivin G.P. Cardell E.L. Doetschman T. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes Development 1997 124 2659 2670 9217007 PMC3850286
  16. [17]Fabregat I. Moreno-Càceres J. Sánchez A. Dooley S. Dewidar B. Giannelli G. Ten Dijke P. IT-LIVER Consortium TGF-β signalling and liver disease FEBS J. 2016 283 2219 2232 10.1111/febs.13665 26807763 · DOI · Paper page
  17. [18]Dropmann A. Dediulia T. Breitkopf-Heinlein K. Korhonen H. Janicot M. Weber S.N. Thomas M. Piiper A. Bertran E. Fabregat I. TGF-β1 and TGF-β2 abundance in liver diseases of mice and men Oncotarget 2016 7 19499 19518 10.18632/oncotarget.6967 26799667 PMC4991397 · DOI
  18. [19]Abd El-Meguid M. Dawood R.M. Mokhles M.A. El Awady M.K. Extrahepatic upregulation of transforming growth factor beta 2 in HCV genotype 4-induced liver fibrosis J. Int. Soc. Interferon Cytokine Res. 2018 38 341 347 10.1089/jir.2018.0045 30130153 · DOI
  19. [20]Chida T. Ito M. Nakashima K. Kanegae Y. Aoshima T. Takabayashi S. Kawata K. Nakagawa Y. Yamamoto M. Shimano H. Critical role of CREBH-mediated induction of transforming growth factor β2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells Hepatology. 2017 66 1430 1443 10.1002/hep.29319 28621467 · DOI
  20. [21]Shi M. Zhu J. Wang R. Chen X. Mi L. Walz T. Springer T.A. Latent TGF-β structure and activation Nature 2011 474 343 349 10.1038/nature10152 21677751 PMC4717672 · DOI · Paper page
  21. [23]Khan Z. Marshall J.F. The role of integrins in TGFβ activation in the tumour stroma Cell Tissue Res. 2016 365 657 673 10.1007/s00441-016-2474-y 27515461 PMC5010607 · DOI
  22. [24]Nishimura S.L. Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders Am. J. Pathol. 2009 175 1362 1370 10.2353/ajpath.2009.090393 19729474 PMC2751532 · DOI
  23. [25]Fan W. Liu T. Chen W. Hammad S. Longerich T. Fu Y. Li N. He Y. Liu C. Zhang Y. ECM1 Prevents activation of transforming growth factor beta, hepatic stellate cells, and fibrogenesis in mice Gastroenterology 2019 157 1352 1367 10.1053/j.gastro.2019.07.036 31362006 · DOI
  24. [26]Carthy J.M. TGFβ signaling and the control of myofibroblast differentiation: Implications for chronic inflammatory disorders J. Cell. Physiol. 2018 233 98 106 10.1002/jcp.25879 28247933 · DOI
  25. [27]Heldin C.-H. Transforming Growth Factor-β Signaling TGF-β in Human Disease Moustakas A. Miyazawa K. Springer Tokyo, Japan 2013 3 32
  26. [28]Levy L. Hill C.S. Smad4 dependency defines two classes of transforming growth factor β (TGF-β) target genes and distinguishes TGF-β-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses Mol. Cell. Biol. 2005 25 8108 8125 10.1128/MCB.25.18.8108-8125.2005 16135802 PMC1234333 · DOI
  27. [29]Moustakas A. Heldin C.-H. Non-Smad TGF-beta signals J. Cell Sci. 2005 118 3573 3584 10.1242/jcs.02554 16105881 · DOI
  28. [30]Zhang Y.E. Non-Smad pathways in TGF-beta signaling Cell Res. 2009 19 128 139 10.1038/cr.2008.328 19114990 PMC2635127 · DOI
  29. [31]Zhang Y.E. Non-Smad Signaling Pathways of the TGF-β Family Cold Spring Harb. Perspect. Biol. 2017 9 a022129 10.1101/cshperspect.a022129 27864313 PMC5287080 · DOI
  30. [32]Lee M.-S. Ko S.-G. Kim H.-P. Kim Y.-B. Lee S.-Y. Kim S.-G. Jong H.-S. Kim T.-Y. Lee J.W. Bang Y.-J. Smad2 mediates Erk1/2 activation by TGF-beta1 in suspended, but not in adherent, gastric carcinoma cells Int. J. Oncol. 2004 24 1229 1234 15067346
  31. [33]Zhang L. Duan C.J. Binkley C. Li G. Uhler M.D. Logsdon C.D. Simeone D.M. A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A Mol. Cell. Biol. 2004 24 2169 2180 10.1128/MCB.24.5.2169-2180.2004 14966294 PMC350541 · DOI
  32. [34]Perlman R. Schiemann W.P. Brooks M.W. Lodish H.F. Weinberg R.A. TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation Nat. Cell Biol. 2001 3 708 714 10.1038/35087019 11483955 · DOI
  33. [35]Kretzschmar M. Doody J. Massagué J. Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1 Nature 1997 389 618 622 10.1038/39348 9335504 · DOI
  34. [37]Yoshida K. Matsuzaki K. Murata M. Yamaguchi T. Suwa K. Okazaki K. Clinico-Pathological importance of TGF-β/phospho-smad signaling during human hepatic fibrocarcinogenesis Cancers 2018 10 183 10.3390/cancers10060183 29874844 PMC6025395 · DOI
  35. [38]Simeone D.M. Zhang L. Graziano K. Nicke B. Pham T. Schaefer C. Logsdon C.D. Smad4 mediates activation of mitogen-activated protein kinases by TGF-beta in pancreatic acinar cells Am. J. Physiol. Cell Physiol. 2001 281 C311 C319 10.1152/ajpcell.2001.281.1.C311 11401854 · DOI
  36. [39]Olsson N. Piek E. Sundström M. ten Dijke P. Nilsson G. Transforming growth factor-beta-mediated mast cell migration depends on mitogen-activated protein kinase activity Cell. Signal. 2001 13 483 490 10.1016/S0898-6568(01)00176-0 11516623 · DOI
  37. [40]Lee M.K. Pardoux C. Hall M.C. Lee P.S. Warburton D. Qing J. Smith S.M. Derynck R. TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcA Embo J. 2007 26 3957 3967 10.1038/sj.emboj.7601818 17673906 PMC1994119 · DOI
  38. [41]Xu F. Liu C. Zhou D. Zhang L. TGF-β/SMAD Pathway and Its Regulation in Hepatic Fibrosis J. Histochem. Cytochem. 2016 64 157 167 10.1369/0022155415627681 26747705 PMC4810800 · DOI
  39. [42]Xu F. Zhou D. Meng X. Wang X. Liu C. Huang C. Li J. Zhang L. Smad2 increases the apoptosis of activated human hepatic stellate cells induced by TRAIL Int. Immunopharmacol. 2016 32 76 86 10.1016/j.intimp.2016.01.013 26802603 · DOI
  40. [43]Khalil H. Kanisicak O. Prasad V. Correll R.N. Fu X. Schips T. Vagnozzi R.J. Liu R. Huynh T. Lee S.-J. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis J. Clin. Investig. 2017 127 3770 3783 10.1172/JCI94753 28891814 PMC5617658 · DOI · Paper page
  41. [44]Carthy J.M. Sundqvist A. Heldin A. van Dam H. Kletsas D. Heldin C.-H. Moustakas A. Tamoxifen inhibits TGF-β-mediated activation of myofibroblasts by blocking non-smad signaling through ERK1/2 J. Cell. Physiol. 2015 230 3084 3092 10.1002/jcp.25049 26096876 · DOI
  42. [45]Ard S. Reed E.B. Smolyaninova L.V. Orlov S.N. Mutlu G.M. Guzy R.D. Dulin N.O. Sustained smad2 phosphorylation is required for myofibroblast transformation in response to TGF-β Am. J. Respir. Cell Mol. Biol. 2019 60 367 369 10.1165/rcmb.2018-0252LE 30821500 PMC6397974 · DOI
  43. [46]Park S.H. Fine tuning and cross-talking of TGF-beta signal by inhibitory Smads J. Biochem. Mol. Biol. 2005 38 9 16 15715940
  44. [47]Goto K. Kamiya Y. Imamura T. Miyazono K. Miyazawa K. Selective inhibitory effects of Smad6 on bone morphogenetic protein type I receptors J. Biol. Chem. 2007 282 20603 20611 10.1074/jbc.M702100200 17493940 · DOI
  45. [48]Shi W. Sun C. He B. Xiong W. Shi X. Yao D. Cao X. GADD34–PP1c recruited by Smad7 dephosphorylates TGFβ type I receptor J. Cell Biol. 2004 164 291 300 10.1083/jcb.200307151 14718519 PMC2172339 · DOI
  46. [49]Kavsak P. Rasmussen R.K. Causing C.G. Bonni S. Zhu H. Thomsen G.H. Wrana J.L. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation Mol. Cell 2000 6 1365 1375 10.1016/S1097-2765(00)00134-9 11163210 · DOI
  47. [50]Malonis R.J. Fu W. Jelcic M.J. Thompson M. Canter B.S. Tsikitis M. Esteva F.J. Sánchez I. RNF11 sequestration of the E3 ligase SMURF2 on membranes antagonizes SMAD7 down-regulation of transforming growth factor β signaling J. Biol. Chem. 2017 292 7435 7451 10.1074/jbc.M117.783662 28292929 PMC5418044 · DOI
  48. [51]Zhang Z. Fan Y. Xie F. Zhou H. Jin K. Shao L. Shi W. Fang P. Yang B. van Dam H. Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7 Nat. Commun. 2017 8 2116 10.1038/s41467-017-02029-7 29235476 PMC5727433 · DOI
  49. [52]Chandhoke A.S. Karve K. Dadakhujaev S. Netherton S. Deng L. Bonni S. The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial–mesenchymal transition in a sumoylation-regulated manner Cell Death Differ. 2016 23 876 888 10.1038/cdd.2015.152 26679521 PMC4832106 · DOI
  50. [53]Shihata W.A. Putra M.R.A. Chin-Dusting J.P.F. Is there a potential therapeutic role for caveolin-1 in fibrosis? Front. Pharm. 2017 8 567 10.3389/fphar.2017.00567 28970796 PMC5609631 · DOI
  51. [54]Le Roy C. Wrana J.L. Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling Nat. Rev. Mol. Cell Biol. 2005 6 112 126 10.1038/nrm1571 15687999 · DOI
  52. [55]Chen Y.-G. Endocytic regulation of TGF-beta signaling Cell Res. 2009 19 58 70 10.1038/cr.2008.315 19050695 · DOI
  53. [56]Meyer C. Godoy P. Bachmann A. Liu Y. Barzan D. Ilkavets I. Maier P. Herskind C. Hengstler J.G. Dooley S. Distinct role of endocytosis for Smad and non-Smad TGF-β signaling regulation in hepatocytes J. Hepatol. 2011 55 369 378 10.1016/j.jhep.2010.11.027 21184784 · DOI
  54. [57]Ji D.-G. Zhang Y. Yao S.-M. Zhai X.-J. Zhang L.-R. Zhang Y.-Z. Li H. Cav-1 deficiency promotes liver fibrosis in carbon tetrachloride (CCl4)-induced mice by regulation of oxidative stress and inflammation responses Biomed. Pharm. Biomed. Pharm. 2018 102 26 33 10.1016/j.biopha.2018.03.016 29549726 · DOI
  55. [58]Lu J. Zhang J. Wang Y. Sun Q. Caveolin-1 scaffolding domain peptides alleviate liver fibrosis by inhibiting tgf-β1/smad signaling in mice Int. J. Mol. Sci. 2018 19 1729 10.3390/ijms19061729 29891777 PMC6032240 · DOI
  56. [59]Meyer C. Liu Y. Kaul A. Peipe I. Dooley S. Caveolin-1 abrogates TGF-β mediated hepatocyte apoptosis Cell Death Dis. 2013 4 e466 10.1038/cddis.2012.204 23328673 PMC3563992 · DOI
  57. [60]Meyer C. Dzieran J. Liu Y. Schindler F. Munker S. Müller A. Coulouarn C. Dooley S. Distinct dedifferentiation processes affect caveolin-1 expression in hepatocytes Cell Commun. Signal. 2013 11 6 10.1186/1478-811X-11-6 23339737 PMC3598962 · DOI
  58. [61]Li M. Chen D. Huang H. Wang J. Wan X. Xu C. Li C. Ma H. Yu C. Li Y. Caveolin1 protects against diet induced hepatic lipid accumulation in mice PLoS ONE 2017 12 e0178748 10.1371/journal.pone.0178748 28570612 PMC5453590 · DOI
  59. [62]Yang Y.M. Noureddin M. Liu C. Ohashi K. Kim S.Y. Ramnath D. Powell E.E. Sweet M.J. Roh Y.S. Hsin I.-F. Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis Sci. Transl. Med. 2019 11 eaat9284 10.1126/scitranslmed.aat9284 31189722 PMC6589184 · DOI · Paper page
  60. [63]Zhang D.-W. Zhao Y.-X. Wei D. Li Y.-L. Zhang Y. Wu J. Xu J. Chen C. Tang H. Zhang W. HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis J. Hepatol. 2012 57 1283 1291 10.1016/j.jhep.2012.07.042 22878468 · DOI
  61. [64]Li H.-Y. Ju D. Zhang D.-W. Li H. Kong L.-M. Guo Y. Li C. Wang X.-L. Chen Z.-N. Bian H. Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis Sci. Rep. 2015 5 16552 10.1038/srep16552 26559755 PMC4642271 · DOI
  62. [65]Shibanuma M. Mashimo J. Kuroki T. Nose K. Characterization of the TGF beta 1-inducible hic-5 gene that encodes a putative novel zinc finger protein and its possible involvement in cellular senescence J. Biol. Chem. 1994 269 26767 26774 7929412
  63. [66]Varney S.D. Betts C.B. Zheng R. Wu L. Hinz B. Zhou J. Van De Water L. Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation J. Cell Sci. 2016 129 774 787 10.1242/jcs.170589 26759173 PMC4760373 · DOI
  64. [67]Lei X.-F. Fu W. Kim-Kaneyama J.-R. Omoto T. Miyazaki T. Li B. Miyazaki A. Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice J. Hepatol. 2016 64 110 117 10.1016/j.jhep.2015.08.026 26334580 · DOI
  65. [68]Kladney R.D. Cui X. Bulla G.A. Brunt E.M. Fimmel C.J. Expression of GP73, a resident Golgi membrane protein, in viral and nonviral liver disease Hepatology 2002 35 1431 1440 10.1053/jhep.2002.32525 12029628 · DOI
  66. [69]Yang X. Wei C. Liu N. Wu F. Chen J. Wang C. Sun Z. Wang Y. Liu L. Zhang X. GP73, a novel TGF-β target gene, provides selective regulation on Smad and non-Smad signaling pathways Biochim. Biophys. Acta Mol. Cell Res. 2019 1866 588 597 10.1016/j.bbamcr.2019.01.001 30615900 · DOI
  67. [70]Earl L.A. Bi S. Baum L.G. Galectin multimerization and lattice formation are regulated by linker region structure Glycobiology 2011 21 6 12 10.1093/glycob/cwq144 20864568 PMC2998985 · DOI
  68. [71]Wu M.-H. Hong H.-C. Hong T.-M. Chiang W.-F. Jin Y.-T. Chen Y.-L. Targeting galectin-1 in carcinoma-associated fibroblasts inhibits oral squamous cell carcinoma metastasis by downregulating MCP-1/CCL2 expression Clin. Cancer Res. 2011 17 1306 1316 10.1158/1078-0432.CCR-10-1824 21385934 · DOI
  69. [72]Tsutsumi T. Suzuki T. Moriya K. Shintani Y. Fujie H. Miyoshi H. Matsuura Y. Koike K. Miyamura T. Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice Hepatology 2003 38 820 828 10.1002/hep.1840380408 14512869 · DOI
  70. [73]Wu M.-H. Chen Y.-L. Lee K.-H. Chang C.-C. Cheng T.-M. Wu S.-Y. Tu C.-C. Tsui W.-L. Glycosylation-dependent galectin-1/neuropilin-1 interactions promote liver fibrosis through activation of TGF-β- and PDGF-like signals in hepatic stellate cells Sci. Rep. 2017 7 11006 10.1038/s41598-017-11212-1 28887481 PMC5591297 · DOI
  71. [74]Chen Y. Rui B.-B. Tang L.-Y. Hu C.-M. Lipin family proteins—Key regulators in lipid metabolism Ann. Nutr. Metab. 2015 66 10 18 10.1159/000368661 25678092 · DOI
  72. [75]Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence J.C. Kelly D.P. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway Cell Metab. 2006 4 199 210 10.1016/j.cmet.2006.08.005 16950137 · DOI
  73. [76]Jang C.H. Kim K.M. Yang J.H. Cho S.S. Kim S.J. Shin S.M. Cho I.J. Ki S.H. The Role of Lipin-1 in the Regulation of Fibrogenesis and TGF-β Signaling in Hepatic Stellate Cells Toxicol. Sci. 2016 153 28 38 10.1093/toxsci/kfw109 27345520 · DOI
  74. [77]Wang Y. Shen R.-W. Han B. Li Z. Xiong L. Zhang F.-Y. Cong B.-B. Zhang B. Notch signaling mediated by TGF-β/Smad pathway in concanavalin A-induced liver fibrosis in rats World J. Gastroenterol. 2017 23 2330 2336 10.3748/wjg.v23.i13.2330 28428712 PMC5385399 · DOI
  75. [78]Shen Z. Liu Y. Dewidar B. Hu J. Park O. Feng T. Xu C. Yu C. Li Q. Meyer C. Delta-like ligand 4 modulates liver damage by down-regulating chemokine expression Am. J. Pathol. 2016 186 1874 1889 10.1016/j.ajpath.2016.03.010 27171900 PMC4929401 · DOI
  76. [79]Xiong P. Zhang J. Xu D. Zhu J. Li W. Liu J. Liu F. Positive feedback loop of YB-1 interacting with Smad2 promotes liver fibrosis Biochem. Biophys. Res. Commun. 2017 484 753 761 10.1016/j.bbrc.2017.01.148 28153731 · DOI
  77. [80]Kolliopoulos C. Raja E. Razmara M. Heldin P. Heldin C.-H. Moustakas A. van der Heide L.P. Transforming growth factor β (TGFβ) induces NUAK kinase expression to fine-tune its signaling output J. Biol. Chem. 2019 294 4119 4136 10.1074/jbc.RA118.004984 30622137 PMC6422081 · DOI
  78. [81]Liu Y. Liu H. Meyer C. Li J. Nadalin S. Königsrainer A. Weng H. Dooley S. ten Dijke P. Transforming growth factor-β (TGF-β)-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation J. Biol. Chem. 2013 288 30708 30719 10.1074/jbc.M113.478685 24005672 PMC3798541 · DOI · Paper page
  79. [82]Tang L.-Y. Heller M. Meng Z. Yu L.-R. Tang Y. Zhou M. Zhang Y.E. Transforming growth factor-β (TGF-β) Directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with the SMAD pathway J. Biol. Chem. 2017 292 4302 4312 10.1074/jbc.M116.773085 28154170 PMC5354477 · DOI
  80. [83]Wang G. Yu Y. Sun C. Liu T. Liang T. Zhan L. Lin X. Feng X.-H. STAT3 selectively interacts with Smad3 to antagonize TGF-β signalling Oncogene 2016 35 4388 4398 10.1038/onc.2015.446 26616859 PMC4885808 · DOI
  81. [84]Yoon J.-H. Sudo K. Kuroda M. Kato M. Lee I.-K. Han J.S. Nakae S. Imamura T. Kim J. Ju J.H. Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation Nat. Commun. 2015 6 7600 10.1038/ncomms8600 26194464 PMC4518312 · DOI
  82. [85]Kim J.-H. Ham S. Lee Y. Suh G.Y. Lee Y.-S. TTC3 contributes to TGF-β1-induced epithelial-mesenchymal transition and myofibroblast differentiation, potentially through SMURF2 ubiquitylation and degradation Cell Death Dis. 2019 10 92 10.1038/s41419-019-1308-8 30696809 PMC6351531 · DOI
  83. [86]Iwaisako K. Jiang C. Zhang M. Cong M. Moore-Morris T.J. Park T.J. Liu X. Xu J. Wang P. Paik Y.-H. Origin of myofibroblasts in the fibrotic liver in mice Proc. Natl. Acad. Sci. USA 2014 111 E3297 E3305 10.1073/pnas.1400062111 25074909 PMC4136601 · DOI · Paper page
  84. [87]Pastan I. Hassan R. Discovery of mesothelin and exploiting it as a target for immunotherapy Cancer Res. 2014 74 2907 2912 10.1158/0008-5472.CAN-14-0337 24824231 PMC4062095 · DOI
  85. [88]Koyama Y. Wang P. Liang S. Iwaisako K. Liu X. Xu J. Zhang M. Sun M. Cong M. Karin D. Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis J. Clin. Investig. 2017 127 1254 1270 10.1172/JCI88845 28287406 PMC5373891 · DOI
  86. [89]Herrera B. Addante A. Sánchez A. BMP Signalling at the crossroad of liver fibrosis and regeneration Int. J. Mol. Sci. 2017 19 39 10.3390/ijms19010039 29295498 PMC5795989 · DOI
  87. [90]Breitkopf-Heinlein K. Meyer C. König C. Gaitantzi H. Addante A. Thomas M. Wiercinska E. Cai C. Li Q. Wan F. BMP-9 interferes with liver regeneration and promotes liver fibrosis Gut 2017 66 939 954 10.1136/gutjnl-2016-313314 28336518 · DOI
  88. [91]Chung Y.-H. Huang Y.-H. Chu T.-H. Chen C.-L. Lin P.-R. Huang S.-C. Wu D.-C. Huang C.-C. Hu T.-H. Kao Y.-H. BMP-2 restoration aids in recovery from liver fibrosis by attenuating TGF-β1 signaling Lab. Investig. J. Tech. Methods Pathol. 2018 98 999 1013 10.1038/s41374-018-0069-9 29789683 · DOI
  89. [92]Zhang Y.-Q. Wan L.-Y. He X.-M. Ni Y.-R. Wang C. Liu C.-B. Wu J.-F. Gremlin1 Accelerates Hepatic Stellate Cell Activation Through Upregulation of TGF-Beta Expression DNA Cell Biol. 2017 36 603 610 10.1089/dna.2017.3707 28467108 · DOI
  90. [93]Navarro-Corcuera A. López-Zabalza M.J. Martínez-Irujo J.J. Álvarez-Sola G. Ávila M.A. Iraburu M.J. Ansorena E. Montiel-Duarte C. Role of AGAP2 in the profibrogenic effects induced by TGFβ in LX-2 hepatic stellate cells Biochim. Biophys. Acta Mol. Cell Res. 2019 1866 673 685 10.1016/j.bbamcr.2019.01.008 30660615 · DOI
  91. [94]Römisch J. Factor VII activating protease (FSAP): A novel protease in hemostasis Biol. Chem. 2002 383 1119 1124 10.1515/BC.2002.121 12437095 · DOI
  92. [95]Leiting S. Seidl S. Martinez-Palacian A. Muhl L. Kanse S.M. Transforming growth factor-β (TGF-β) inhibits the expression of factor vii-activating protease (FSAP) in hepatocytes J. Biol. Chem. 2016 291 21020 21028 10.1074/jbc.M116.744631 27462075 PMC5076512 · DOI
  93. [96]Borkham-Kamphorst E. Zimmermann H.W. Gassler N. Bissels U. Bosio A. Tacke F. Weiskirchen R. Kanse S.M. Factor VII activating protease (FSAP) exerts anti-inflammatory and anti-fibrotic effects in liver fibrosis in mice and men J. Hepatol. 2013 58 104 111 10.1016/j.jhep.2012.09.007 22989567 · DOI
  94. [97]Wasmuth H.E. Tag C.G. Van de Leur E. Hellerbrand C. Mueller T. Berg T. Puhl G. Neuhaus P. Samuel D. Trautwein C. The Marburg I variant (G534E) of the factor VII-activating protease determines liver fibrosis in hepatitis C infection by reduced proteolysis of platelet-derived growth factor BB Hepatology 2009 49 775 780 10.1002/hep.22707 19105210 · DOI
  95. [98]Spanjer A.I.R. Baarsma H.A. Oostenbrink L.M. Jansen S.R. Kuipers C.C. Lindner M. Postma D.S. Meurs H. Heijink I.H. Gosens R. TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8 FASEB J. 2016 30 1823 1835 10.1096/fj.201500129 26849959 · DOI
  96. [99]Beljaars L. Daliri S. Dijkhuizen C. Poelstra K. Gosens R. WNT-5A regulates TGF-β-related activities in liver fibrosis Am. J. Physiol. Gastrointest. Liver Physiol. 2017 312 G219 G227 10.1152/ajpgi.00160.2016 28057611 · DOI
  97. [100]Augustin H.G. Koh G.Y. Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology Science 2017 357 eaal2379 10.1126/science.aal2379 28775214 · DOI
  98. [101]Karin D. Koyama Y. Brenner D. Kisseleva T. The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis Differ. Res. Biol. Divers. 2016 92 84 92 10.1016/j.diff.2016.07.001 27591095 PMC5079826 · DOI
  99. [102]Sun M. Kisseleva T. Reversibility of liver fibrosis Clin. Res. Hepatol. Gastroenterol. 2015 39 S60 S63 10.1016/j.clinre.2015.06.015 26206574 PMC4636085 · DOI
  100. [103]Bataller R. Brenner D.A. Liver fibrosis J. Clin. Investig. 2005 115 209 218 10.1172/JCI24282 15690074 PMC546435 · DOI · Paper page
  101. [104]Puche J.E. Saiman Y. Friedman S.L. Hepatic stellate cells and liver fibrosis Compr. Physiol. 2013 3 1473 1492 24265236
  102. [105]Heymann F. Trautwein C. Tacke F. Monocytes and macrophages as cellular targets in liver fibrosis Inflamm. Allergy Drug Targets 2009 8 307 318 10.2174/187152809789352230 19534673 · DOI
  103. [106]Krenkel O. Tacke F. Liver macrophages in tissue homeostasis and disease Nat. Rev. Immunol. 2017 17 306 321 10.1038/nri.2017.11 28317925 · DOI · Paper page
  104. [107]Schuppan D. Ruehl M. Somasundaram R. Hahn E.G. Matrix as a modulator of hepatic fibrogenesis Semin. Liver Dis. 2001 21 351 372 10.1055/s-2001-17556 11586465 · DOI
  105. [108]Henderson N.C. Arnold T.D. Katamura Y. Giacomini M.M. Rodriguez J.D. McCarty J.H. Pellicoro A. Raschperger E. Betsholtz C. Ruminski P.G. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs Nat. Med. 2013 19 1617 1624 10.1038/nm.3282 24216753 PMC3855865 · DOI · Paper page
  106. [109]Olaso E. Ikeda K. Eng F.J. Xu L. Wang L.H. Lin H.C. Friedman S.L. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells J. Clin. Investig. 2001 108 1369 1378 10.1172/JCI200112373 11696582 PMC209436 · DOI
  107. [111]Greenhalgh S.N. Matchett K.P. Taylor R.S. Huang K. Li J.T. Saeteurn K. Donnelly M.C. Simpson E.E.M. Pollack J.L. Atakilit A. Loss of integrin αvβ8 in murine hepatocytes accelerates liver regeneration Am. J. Pathol. 2019 189 258 271 10.1016/j.ajpath.2018.10.007 30448409 PMC6360354 · DOI
  108. [112]Rognoni E. Ruppert R. Fässler R. The kindlin family: Functions, signaling properties and implications for human disease J. Cell Sci. 2016 129 17 27 10.1242/jcs.161190 26729028 · DOI
  109. [113]Yu J. Hu Y. Gao Y. Li Q. Zeng Z. Li Y. Chen H. Kindlin-2 regulates hepatic stellate cells activation and liver fibrogenesis Cell Death Discov. 2018 4 34 10.1038/s41420-018-0095-9 30245857 PMC6135746 · DOI
  110. [114]Zollinger A.J. Smith M.L. Fibronectin, the extracellular glue Matrix Biol. J. Int. Soc. Matrix Biol. 2017 60–61 27 37 10.1016/j.matbio.2016.07.011 27496349 · DOI
  111. [115]Klingberg F. Chau G. Walraven M. Boo S. Koehler A. Chow M.L. Olsen A.L. Im M. Lodyga M. Wells R.G. The fibronectin ED-A domain enhances recruitment of latent TGF-β-binding protein-1 to the fibroblast matrix J. Cell Sci. 2018 131 jcs201293 10.1242/jcs.201293 29361522 PMC5897715 · DOI
  112. [116]Peters J.H. Hynes R.O. Fibronectin isoform distribution in the mouse. I. The alternatively spliced EIIIB, EIIIA, and V segments show widespread codistribution in the developing mouse embryo Cell Adhes. Commun. 1996 4 103 125 10.3109/15419069609010766 8937746 · DOI
  113. [117]Zent J. Guo L.-W. Signaling Mechanisms of Myofibroblastic Activation: Outside-in and Inside-Out Cell. Physiol. Biochem. 2018 49 848 868 10.1159/000493217 30184544 PMC6611700 · DOI
  114. [118]Muro A.F. Moretti F.A. Moore B.B. Yan M. Atrasz R.G. Wilke C.A. Flaherty K.R. Martinez F.J. Tsui J.L. Sheppard D. An essential role for fibronectin extra type III domain A in pulmonary fibrosis Am. J. Respir. Crit. Care Med. 2008 177 638 645 10.1164/rccm.200708-1291OC 18096707 PMC2267338 · DOI · Paper page
  115. [119]Kawelke N. Vasel M. Sens C. von Au A. Dooley S. Nakchbandi I.A. Fibronectin protects from excessive liver fibrosis by modulating the availability of and responsiveness of stellate cells to active TGF-β PLoS ONE 2011 6 e28181 10.1371/journal.pone.0028181 22140539 PMC3225392 · DOI
  116. [120]Altrock E. Sens C. Wuerfel C. Vasel M. Kawelke N. Dooley S. Sottile J. Nakchbandi I.A. Inhibition of fibronectin deposition improves experimental liver fibrosis J. Hepatol. 2015 62 625 633 10.1016/j.jhep.2014.06.010 24946284 · DOI
  117. [121]Phanish M.K. Heidebrecht F. Nabi M.E. Shah N. Niculescu-Duvaz I. Dockrell M.E.C. The regulation of TGFβ1 Induced fibronectin eda exon alternative splicing in human renal proximal tubule epithelial cells J. Cell. Physiol. 2015 230 286 295 10.1002/jcp.24703 24962218 · DOI
  118. [122]Li J. Wang Y. Ma M. Jiang S. Zhang X. Zhang Y. Yang X. Xu C. Tian G. Li Q. Autocrine CTHRC1 activates hepatic stellate cells and promotes liver fibrosis by activating TGF-β signaling EBioMedicine 2019 40 43 55 10.1016/j.ebiom.2019.01.009 30639416 PMC6412555 · DOI
  119. [123]Santos A. Lagares D. Matrix stiffness: The conductor of organ fibrosis Curr. Rheumatol. Rep. 2018 20 2 10.1007/s11926-018-0710-z 29349703 · DOI
  120. [125]Caliari S.R. Perepelyuk M. Soulas E.M. Lee G.Y. Wells R.G. Burdick J.A. Gradually softening hydrogels for modeling hepatic stellate cell behavior during fibrosis regression Integr. Biol. Quant. Biosci. Nano Macro 2016 8 720 728 10.1039/C6IB00027D 27162057 PMC4905794 · DOI
  121. [126]Peterová E. Mrkvicová A. Podmolíková L. Řezáčová M. Kanta J. The role of cytokines TGF-beta1 and FGF-1 in the expression of characteristic markers of rat liver myofibroblasts cultured in three-dimensional collagen gel Physiol. Res. 2016 65 661 672 27429124
  122. [127]Siegel R.C. Pinnell S.R. Martin G.R. Cross-linking of collagen and elastin. Properties of lysyl oxidase Biochemistry 1970 9 4486 4492 10.1021/bi00825a004 5474144 · DOI · Paper page
  123. [128]Liu S.B. Ikenaga N. Peng Z.-W. Sverdlov D.Y. Greenstein A. Smith V. Schuppan D. Popov Y. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice FASEB J. 2016 30 1599 1609 10.1096/fj.14-268425 26700732 · DOI · Paper page
  124. [129]Ma L. Zeng Y. Wei J. Yang D. Ding G. Liu J. Shang J. Kang Y. Ji X. Knockdown of LOXL1 inhibits TGF-β1-induced proliferation and fibrogenesis of hepatic stellate cells by inhibition of Smad2/3 phosphorylation Biomed. Pharm. Biomed. Pharm. 2018 107 1728 1735 10.1016/j.biopha.2018.08.156 30257391 · DOI
  125. [130]Mesarwi O.A. Shin M.-K. Drager L.F. Bevans-Fonti S. Jun J.C. Putcha N. Torbenson M.S. Pedrosa R.P. Lorenzi-Filho G. Steele K.E. Lysyl Oxidase as a serum biomarker of liver fibrosis in patients with severe obesity and obstructive sleep apnea Sleep 2015 38 1583 1591 10.5665/sleep.5052 26085300 PMC4576332 · DOI
  126. [131]Wang Z. Perez M. Lee E.-S. Kojima S. Griffin M. The functional relationship between transglutaminase 2 and transforming growth factor β1 in the regulation of angiogenesis and endothelial-mesenchymal transition Cell Death Dis. 2017 8 e3032 10.1038/cddis.2017.399 28880274 PMC5636968 · DOI
  127. [132]Verderio E. Gaudry C. Gross S. Smith C. Downes S. Griffin M. Regulation of cell surface tissue transglutaminase: Effects on matrix storage of latent transforming growth factor-beta binding protein-1 J. Histochem. Cytochem. 1999 47 1417 1432 10.1177/002215549904701108 10544215 · DOI
  128. [133]Weiskirchen R. Tacke F. Liver fibrosis: From pathogenesis to novel therapies Dig. Dis. 2016 34 410 422 10.1159/000444556 27170396 · DOI
  129. [135]Cai X. Li Z. Zhang Q. Qu Y. Xu M. Wan X. Lu L. CXCL6-EGFR-induced Kupffer cells secrete TGF-β1 promoting hepatic stellate cell activation via the SMAD2/BRD4/C-MYC/EZH2 pathway in liver fibrosis J. Cell. Mol. Med. 2018 22 5050 5061 10.1111/jcmm.13787 30106235 PMC6156397 · DOI
  130. [136]Fabre T. Molina M.F. Soucy G. Goulet J.-P. Willems B. Villeneuve J.-P. Bilodeau M. Shoukry N.H. Type 3 cytokines IL-17A and IL-22 drive TGF-β-dependent liver fibrosis Sci. Immunol. 2018 3 e7754 10.1126/sciimmunol.aar7754 30366940 · DOI · Paper page
  131. [137]Shi J. Zhao J. Zhang X. Cheng Y. Hu J. Li Y. Zhao X. Shang Q. Sun Y. Tu B. Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-β-dependent emperipolesis in HBV cirrhotic patients Sci. Rep. 2017 7 44544 10.1038/srep44544 28291251 PMC5349579 · DOI
  132. [138]Ng C.P. Hinz B. Swartz M.A. Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro J. Cell Sci. 2005 118 4731 4739 10.1242/jcs.02605 16188933 · DOI
  133. [139]Nithiananthan S. Crawford A. Knock J.C. Lambert D.W. Whawell S.A. Physiological fluid flow moderates fibroblast responses to TGF-β1 J. Cell. Biochem. 2017 118 878 890 10.1002/jcb.25767 27748539 · DOI
  134. [140]Ansorge M. Sapudom J. Chkolnikov M. Wilde M. Anderegg U. Möller S. Schnabelrauch M. Pompe T. Mimicking paracrine TGFβ1 Signals during myofibroblast differentiation in 3D Collagen networks Sci. Rep. 2017 7 5664 10.1038/s41598-017-05912-x 28720779 PMC5515936 · DOI
  135. [141]Zi Z. Feng Z. Chapnick D.A. Dahl M. Deng D. Klipp E. Moustakas A. Liu X. Quantitative analysis of transient and sustained transforming growth factor-β signaling dynamics Mol. Syst. Biol. 2011 7 492 10.1038/msb.2011.22 21613981 PMC3130555 · DOI
  136. [142]Feng Z. Zi Z. Liu X. Measuring TGF-β ligand dynamics in culture medium Methods Mol. Biol. 2016 1344 379 389 26520139 PMC6116904
  137. [143]Hara M. Kirita A. Kondo W. Matsuura T. Nagatsuma K. Dohmae N. Ogawa S. Imajoh-Ohmi S. Friedman S.L. Rifkin D.B. LAP degradation product reflects plasma kallikrein-dependent TGF-β activation in patients with hepatic fibrosis SpringerPlus 2014 3 221 10.1186/2193-1801-3-221 24877031 PMC4033717 · DOI
  138. [144]Hara M. Inoue I. Yamazaki Y. Kirita A. Matsuura T. Friedman S.L. Rifkin D.B. Kojima S. L59 TGF-β LAP degradation products serve as a promising blood biomarker for liver fibrogenesis in mice Fibrogenesis Tissue Repair 2015 8 17 10.1186/s13069-015-0034-9 26379781 PMC4570586 · DOI
  139. [145]Novo E. Parola M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis Fibrogenesis Tissue Repair 2008 1 5 10.1186/1755-1536-1-5 19014652 PMC2584013 · DOI
  140. [147]Liu R.-M. Desai L.P. Reciprocal regulation of TGF-β and reactive oxygen species: A perverse cycle for fibrosis Redox Biol. 2015 6 565 577 10.1016/j.redox.2015.09.009 26496488 PMC4625010 · DOI
  141. [148]Wu Y. Wang W. Peng X.-M. He Y. Xiong Y.-X. Liang H.-F. Chu L. Zhang B.-X. Ding Z.-Y. Chen X.-P. Rapamycin Upregulates connective tissue growth factor expression in hepatic progenitor cells through TGF-β-Smad2 dependent signaling Front. Pharm. 2018 9 877 10.3389/fphar.2018.00877 30135653 PMC6092675 · DOI
  142. [149]Liang S. Kisseleva T. Brenner D.A. The role of NADPH oxidases (NOXs) in liver fibrosis and the activation of myofibroblasts Front. Physiol. 2016 7 17 10.3389/fphys.2016.00017 26869935 PMC4735448 · DOI
  143. [150]Paik Y.-H. Iwaisako K. Seki E. Inokuchi S. Schnabl B. Osterreicher C.H. Kisseleva T. Brenner D.A. The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice Hepatology 2011 53 1730 1741 10.1002/hep.24281 21384410 PMC3082608 · DOI
  144. [151]Matsumoto M. Zhang J. Zhang X. Liu J. Jiang J.X. Yamaguchi K. Taruno A. Katsuyama M. Iwata K. Ibi M. The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease Free Radic. Biol. Med. 2018 115 412 420 10.1016/j.freeradbiomed.2017.12.019 29274380 PMC5969997 · DOI
  145. [152]Sancho P. Mainez J. Crosas-Molist E. Roncero C. Fernández-Rodriguez C.M. Pinedo F. Huber H. Eferl R. Mikulits W. Fabregat I. NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development PLoS ONE 2012 7 e45285 10.1371/journal.pone.0045285 23049784 PMC3458844 · DOI
  146. [153]Andueza A. Garde N. García-Garzón A. Ansorena E. López-Zabalza M.J. Iraburu M.J. Zalba G. Martínez-Irujo J.J. NADPH oxidase 5 promotes proliferation and fibrosis in human hepatic stellate cells Free Radic. Biol. Med. 2018 126 15 26 10.1016/j.freeradbiomed.2018.07.013 30036633 · DOI
  147. [154]Latella G. Redox Imbalance in intestinal fibrosis: Beware of the TGFβ-1, ROS, and Nrf2 connection Dig. Dis. Sci. 2018 63 312 320 10.1007/s10620-017-4887-1 29273848 · DOI
  148. [155]Xu W. Hellerbrand C. Köhler U.A. Bugnon P. Kan Y.-W. Werner S. Beyer T.A. The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis Lab. Investig. J. Tech. Methods Pathol. 2008 88 1068 1078 10.1038/labinvest.2008.75 18679376 · DOI
  149. [156]Oh C.J. Kim J.-Y. Min A.-K. Park K.-G. Harris R.A. Kim H.-J. Lee I.-K. Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling Free Radic. Biol. Med. 2012 52 671 682 10.1016/j.freeradbiomed.2011.11.012 22155056 · DOI
  150. [157]Prestigiacomo V. Suter-Dick L. Nrf2 protects stellate cells from Smad-dependent cell activation PLoS ONE 2018 13 e0201044 10.1371/journal.pone.0201044 30028880 PMC6054401 · DOI
  151. [158]Guan Y. Tan Y. Liu W. Yang J. Wang D. Pan D. Sun Y. Zheng C. NF-E2-related factor 2 suppresses intestinal fibrosis by inhibiting reactive oxygen species-dependent TGF-β1/SMADs pathway Dig. Dis. Sci. 2018 63 366 380 10.1007/s10620-017-4710-z 28815354 · DOI
  152. [159]Chen Q. Zhang H. Cao Y. Li Y. Sun S. Zhang J. Zhang G. Schisandrin B attenuates CCl4-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-β/Smad signaling pathways Drug Des. Dev. 2017 11 2179 2191 10.2147/DDDT.S137507 28794616 PMC5538685 · DOI
  153. [160]Piersma B. Wouters O.Y. de Rond S. Boersema M. Gjaltema R.A.F. Bank R.A. Ascorbic acid promotes a TGFβ1-induced myofibroblast phenotype switch Physiol. Rep. 2017 5 e13324 10.14814/phy2.13324 28904079 PMC5599854 · DOI
  154. [161]Jung B.-J. Yoo H.-S. Shin S. Park Y.-J. Jeon S.-M. Dysregulation of NRF2 in cancer: From Molecular mechanisms to therapeutic opportunities Biomology 2018 26 57 68 10.4062/biomolther.2017.195 29212307 PMC5746038 · DOI
  155. [162]Camarena V. Wang G. The epigenetic role of vitamin C in health and disease Cell. Mol. Life Sci. 2016 73 1645 1658 10.1007/s00018-016-2145-x 26846695 PMC4805483 · DOI
  156. [163]Argemi J. Latasa M.U. Atkinson S.R. Blokhin I.O. Massey V. Gue J.P. Cabezas J. Lozano J.J. Van Booven D. Bell A. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis Nat. Commun. 2019 10 3126 10.1038/s41467-019-11004-3 31311938 PMC6635373 · DOI
  157. [164]Berger S.L. Kouzarides T. Shiekhattar R. Shilatifard A. An operational definition of epigenetics Genes Dev. 2009 23 781 783 10.1101/gad.1787609 19339683 PMC3959995 · DOI
  158. [165]Yu F. Chen B. Fan X. Li G. Dong P. Zheng J. Epigenetically-regulated MicroRNA-9-5p suppresses the activation of hepatic stellate cells via TGFBR1 and TGFBR2 Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharm. 2017 43 2242 2252 10.1159/000484303 29073595 · DOI
  159. [166]Davoodian P. Ravanshad M. Hosseini S.Y. Khanizadeh S. Almasian M. Nejati Zadeh A. Esmaiili Lashgarian H. Effect of TGF-β/smad signaling pathway blocking on expression profiles of miR-335, miR-150, miR-194, miR-27a, and miR-199a of hepatic stellate cells (HSCs) Gastroenterol. Hepatol. Bed Bench 2017 10 112 117 28702135 PMC5495898
  160. [167]Bowen T. Jenkins R.H. Fraser D.J. MicroRNAs, transforming growth factor beta-1, and tissue fibrosis J. Pathol. 2013 229 274 285 10.1002/path.4119 23042530 · DOI
  161. [168]Coll M. El Taghdouini A. Perea L. Mannaerts I. Vila-Casadesús M. Blaya D. Rodrigo-Torres D. Affò S. Morales-Ibanez O. Graupera I. Integrative miRNA and Gene expression profiling analysis of human quiescent hepatic stellate cells Sci. Rep. 2015 5 11549 10.1038/srep11549 26096707 PMC4476106 · DOI
  162. [169]Roderburg C. Luedde M. Vargas Cardenas D. Vucur M. Mollnow T. Zimmermann H.W. Koch A. Hellerbrand C. Weiskirchen R. Frey N. miR-133a mediates TGF-β-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis J. Hepatol. 2013 58 736 742 10.1016/j.jhep.2012.11.022 23183523 · DOI
  163. [170]Roy S. Benz F. Vargas Cardenas D. Vucur M. Gautheron J. Schneider A. Hellerbrand C. Pottier N. Alder J. Tacke F. miR-30c and miR-193 are a part of the TGF-β-dependent regulatory network controlling extracellular matrix genes in liver fibrosis J. Dig. Dis. 2015 16 513 524 10.1111/1751-2980.12266 26120970 · DOI
  164. [171]Brandon-Warner E. Benbow J.H. Swet J.H. Feilen N.A. Culberson C.R. McKillop I.H. deLemos A.S. Russo M.W. Schrum L.W. Adeno-associated virus serotype 2 vector-mediated reintroduction of microrna-19b attenuates hepatic fibrosis Hum. Gene Ther. 2018 29 674 686 10.1089/hum.2017.035 29281894 PMC6004090 · DOI
  165. [172]Feili X. Wu S. Ye W. Tu J. Lou L. MicroRNA-34a-5p inhibits liver fibrosis by regulating TGF-β1/Smad3 pathway in hepatic stellate cells Cell Biol. Int. 2018 42 1370 1376 10.1002/cbin.11022 29957876 · DOI
  166. [173]Zou Y. Li S. Li Z. Song D. Zhang S. Yao Q. MiR-146a attenuates liver fibrosis by inhibiting transforming growth factor-β1 mediated epithelial-mesenchymal transition in hepatocytes Cell. Signal. 2019 58 1 8 10.1016/j.cellsig.2019.01.012 30711634 · DOI
  167. [174]Zou Y. Cai Y. Lu D. Zhou Y. Yao Q. Zhang S. MicroRNA-146a-5p attenuates liver fibrosis by suppressing profibrogenic effects of TGFβ1 and lipopolysaccharide Cell. Signal. 2017 39 1 8 10.1016/j.cellsig.2017.07.016 28739486 · DOI
  168. [175]Wang P. Lei S. Wang X. Xu W. Hu P. Chen F. Zhang X. Yin C. Xie W. MicroRNA-134 deactivates hepatic stellate cells by targeting tgf-β activated kinase 1-binding protein 1 Biochem. Cell Biol. 2019 97 505 512 10.1139/bcb-2018-0211 30645141 · DOI
  169. [176]Tao L. Xue D. Shen D. Ma W. Zhang J. Wang X. Zhang W. Wu L. Pan K. Yang Y. MicroRNA-942 mediates hepatic stellate cell activation by regulating BAMBI expression in human liver fibrosis Arch. Toxicol. 2018 92 2935 2946 10.1007/s00204-018-2278-9 30097701 PMC6590087 · DOI
  170. [177]You K. Li S.-Y. Gong J. Fang J.-H. Zhang C. Zhang M. Yuan Y. Yang J. Zhuang S.-M. MicroRNA-125b promotes hepatic stellate cell activation and liver fibrosis by activating rhoa signaling Mol. Nucleic Acids 2018 12 57 66 10.1016/j.omtn.2018.04.016 30195793 PMC6023793 · DOI
  171. [178]Yu F. Guo Y. Chen B. Dong P. Zheng J. MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7 Lab. Investig. J. Tech. Methods Pathol. 2015 95 781 789 10.1038/labinvest.2015.58 25915722 · DOI
  172. [179]Zhu J. Zhang Z. Zhang Y. Li W. Zheng W. Yu J. Wang B. Chen L. Zhuo Q. Chen L. MicroRNA-212 activates hepatic stellate cells and promotes liver fibrosis via targeting SMAD7 Biochem. Biophys. Res. Commun. 2018 496 176 183 10.1016/j.bbrc.2018.01.019 29307832 · DOI
  173. [180]Tu X. Zheng X. Li H. Cao Z. Chang H. Luan S. Zhu J. Chen J. Zang Y. Zhang J. MicroRNA-30 Protects against carbon tetrachloride-induced liver fibrosis by attenuating transforming growth factor beta signaling in hepatic stellate cells Toxicol. Sci. 2015 146 157 169 10.1093/toxsci/kfv081 25912033 · DOI
  174. [181]Gupta P. Sata T.N. Yadav A.K. Mishra A. Vats N. Hossain M.M. Sanal M.G. Venugopal S.K. TGF-β induces liver fibrosis via miRNA-181a-mediated down regulation of augmenter of liver regeneration in hepatic stellate cells PLoS ONE 2019 14 e0214534 10.1371/journal.pone.0214534 31166951 PMC6550375 · DOI
  175. [182]Yang X. Dan X. Men R. Ma L. Wen M. Peng Y. Yang L. MiR-142-3p blocks TGF-β-induced activation of hepatic stellate cells through targeting TGFβRI Life Sci. 2017 187 22 30 10.1016/j.lfs.2017.08.017 28823564 · DOI
  176. [183]Wei S. Wang Q. Zhou H. Qiu J. Li C. Shi C. Zhou S. Liu R. Lu L. miR-455-3p Alleviates Hepatic Stellate Cell Activation and Liver Fibrosis by Suppressing HSF1 Expression Mol. Nucleic Acids 2019 16 758 769 10.1016/j.omtn.2019.05.001 31150929 PMC6539335 · DOI
  177. [184]Fan Z. Hao C. Li M. Dai X. Qin H. Li J. Xu H. Wu X. Zhang L. Fang M. MKL1 is an epigenetic modulator of TGF-β induced fibrogenesis Biochim. Biophys. Acta 2015 1849 1219 1228 10.1016/j.bbagrm.2015.07.013 26241940 · DOI · Paper page
  178. [185]Hu J. Chen C. Liu Q. Liu B. Song C. Zhu S. Wu C. Liu S. Yu H. Yao D. The role of the miR-31/FIH1 pathway in TGF-β-induced liver fibrosis Clin. Sci. 2015 129 305 317 10.1042/CS20140012 25728779 · DOI
  179. [186]Genz B. Coleman M.A. Irvine K.M. Kutasovic J.R. Miranda M. Gratte F.D. Tirnitz-Parker J.E.E. Olynyk J.K. Calvopina D.A. Weis A. Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells Sci. Rep. 2019 9 8541 10.1038/s41598-019-44865-1 31189969 PMC6561916 · DOI
  180. [187]Peng H. Wan L.-Y. Liang J.-J. Zhang Y.-Q. Ai W.-B. Wu J.-F. The roles of lncRNA in hepatic fibrosis Cell Biosci. 2018 8 63 10.1186/s13578-018-0259-6 30534359 PMC6282372 · DOI
  181. [188]Tang P.M.-K. Zhang Y.-Y. Lan H.-Y. LncRNAs in TGF-β-driven tissue fibrosis Non-Coding RNA 2018 4 26 10.3390/ncrna4040026 30287731 PMC6315857 · DOI
  182. [189]Tu X. Zhang Y. Zheng X. Deng J. Li H. Kang Z. Cao Z. Huang Z. Ding Z. Dong L. TGF-β-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice Sci. Rep. 2017 7 2957 10.1038/s41598-017-03175-0 28592847 PMC5462818 · DOI
  183. [190]Zhang Y. Liu C. Barbier O. Smalling R. Tsuchiya H. Lee S. Delker D. Zou A. Hagedorn C.H. Wang L. Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function Sci. Rep. 2016 6 20559 10.1038/srep20559 26838806 PMC4738356 · DOI
  184. [191]Chen X. Yamamoto M. Fujii K. Nagahama Y. Ooshio T. Xin B. Okada Y. Furukawa H. Nishikawa Y. Differential reactivation of fetal/neonatal genes in mouse liver tumors induced in cirrhotic and non-cirrhotic conditions Cancer Sci. 2015 106 972 981 10.1111/cas.12700 26011625 PMC4556385 · DOI
  185. [192]Zhu J. Luo Z. Pan Y. Zheng W. Li W. Zhang Z. Xiong P. Xu D. Du M. Wang B. H19/miR-148a/USP4 axis facilitates liver fibrosis by enhancing TGF-β signaling in both hepatic stellate cells and hepatocytes J. Cell. Physiol. 2019 234 9698 9710 10.1002/jcp.27656 30362572 · DOI
  186. [193]Song M. Xia L. Sun M. Yang C. Wang F. Circular RNA in Liver: Health and diseases Adv. Exp. Med. Biol. 2018 1087 245 257 30259372
  187. [194]Chen Y. Yuan B. Wu Z. Dong Y. Zhang L. Zeng Z. Microarray profiling of circular RNAs and the potential regulatory role of hsa_circ_0071410 in the activated human hepatic stellate cell induced by irradiation Gene 2017 629 35 42 10.1016/j.gene.2017.07.078 28774651 · DOI
  188. [195]Zhou Y. Lv X. Qu H. Zhao K. Fu L. Zhu L. Ye G. Guo J. Preliminary screening and functional analysis of circular RNAs associated with hepatic stellate cell activation Gene 2018 677 317 323 10.1016/j.gene.2018.08.052 30118889 · DOI
  189. [196]Keene J.D. RNA regulons: Coordination of post-transcriptional events Nat. Rev. Genet. 2007 8 533 543 10.1038/nrg2111 17572691 · DOI · Paper page
  190. [197]Wang S. Jung Y. Hyun J. Friedersdorf M. Oh S.-H. Kim J. Premont R.T. Keene J.D. Diehl A.M. RNA binding proteins control transdifferentiation of hepatic stellate cells into myofibroblasts Cell. Physiol. Biochem. 2018 48 1215 1229 10.1159/000491987 30045014 · DOI
  191. [198]Chen P.-J. Huang C. Meng X.-M. Li J. Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis Biochimie 2015 116 61 69 10.1016/j.biochi.2015.06.016 26116886 · DOI
  192. [199]Hardy T. Mann D.A. Epigenetics in liver disease: From biology to therapeutics Gut 2016 65 1895 1905 10.1136/gutjnl-2015-311292 27624887 PMC5099193 · DOI
  193. [200]Zhou B. Zeng S. Li L. Fan Z. Tian W. Li M. Xu H. Wu X. Fang M. Xu Y. Angiogenic factor with G patch and FHA domains 1 (Aggf1) regulates liver fibrosis by modulating TGF-β signaling Biochim. Biophys. Acta 2016 1862 1203 1213 10.1016/j.bbadis.2016.02.002 26850475 · DOI
  194. [201]Zeybel M. Luli S. Sabater L. Hardy T. Oakley F. Leslie J. Page A. Moran Salvador E. Sharkey V. Tsukamoto H. A proof-of-concept for epigenetic therapy of tissue fibrosis: Inhibition of liver fibrosis progression by 3-deazaneplanocin A Mol. J. Am. Soc. Gene 2017 25 218 231 10.1016/j.ymthe.2016.10.004 28129116 PMC5363305 · DOI
  195. [202]Martin-Mateos R. De Assuncao T.M. Arab J.P. Jalan-Sakrikar N. Yaqoob U. Greuter T. Verma V.K. Mathison A.J. Cao S. Lomberk G. Enhancer of zeste homologue 2 inhibition attenuates TGF-β dependent hepatic stellate cell activation and liver fibrosis Cell. Mol. Gastroenterol. Hepatol. 2019 7 197 209 10.1016/j.jcmgh.2018.09.005 30539787 PMC6282644 · DOI · Paper page
  196. [203]Lin T. Wang S. Shao C. Yuan X. Wandrer F. Bantel H. Marx A. Ebert M. Ding H. Dooley S. THU-375-Transcription factor TRIM33 controls liver progenitor cell towards hepatocyte differentiation through synergizing with SMAD2/3 following massive parenchymal loss J. Hepatol. 2019 70 e318 e319 10.1016/S0618-8278(19)30623-1 · DOI
  197. [204]Wang Y. Zhao L. Jiao F.-Z. Zhang W.-B. Chen Q. Gong Z.-J. Histone deacetylase inhibitor suberoylanilide hydroxamic acid alleviates liver fibrosis by suppressing the transforming growth factor-β1 signal pathway Hepatobiliary Pancreat. Dis. Int. 2018 17 423 429 10.1016/j.hbpd.2018.09.013 30249543 · DOI
  198. [205]Tu A.W. Luo K. Acetylation of Smad2 by the co-activator p300 regulates activin and transforming growth factor beta response J. Biol. Chem. 2007 282 21187 21196 10.1074/jbc.M700085200 17478422 · DOI
  199. [206]Inoue Y. Itoh Y. Abe K. Okamoto T. Daitoku H. Fukamizu A. Onozaki K. Hayashi H. Smad3 is acetylated by p300/CBP to regulate its transactivation activity Oncogene 2007 26 500 508 10.1038/sj.onc.1209826 16862174 · DOI
  200. [207]Janknecht R. Wells N.J. Hunter T. TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300 Genes Dev. 1998 12 2114 2119 10.1101/gad.12.14.2114 9679056 PMC317012 · DOI

200 of 263 shown

Cited by

Sorted by citations

Authors
Dewidar, B., Meyer, C., Dooley, S., & Meindl-Beinker, A. N.
Affiliations
  • Tanta University (EG)
  • Heidelberg University (DE)
Corresponding author
Meindl-Beinker, and Nadja
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2019-11-11
Volume
8
Issue
11
Pages
1419
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells8111419
PMC
PMC6912224
OpenAlex
W2986691533
Cited by
837
References
16
Citations by year
2026: 135 · 2025: 127 · 2024: 143 · 2023: 133 · 2022: 136 · 2021: 118 · 2020: 41 · 2019: 2 · 2018: 2
FWCI
9.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
TGF-beta signaling, hepatic stellate cell activation, liver fibrosis, fibrogenesis, antifibrotic therapy, cellular senescence, reactive oxygen species, epigenetics, circadian rhythm, epithelial-mesenchymal transition, endothelial-to-mesenchymal transition, tumor microenvironment, TGF-β inhibitors, hepatocellular carcinoma, liver cirrhosis
MeSH terms
Animals, Autophagy, Circadian Rhythm, Disease Susceptibility, Energy Metabolism, Gene Expression Regulation, Humans, Liver Cirrhosis, Signal Transduction, Biomarkers, Transforming Growth Factor beta, Cellular Senescence, Oxidative Stress, Epigenesis, Genetic, Hepatic Stellate Cells, Myofibroblasts, Cellular Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review