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Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation

  • Authors:
    • He-Ming Huang
    • Xiao-Ru Zhou
    • Yan-Jun Liu
    • Shi-Jie Fan
    • Li-Ping Liao
    • Jing Huang
    • Cui-Cui Shi
    • Liang Yu
    • Jin-Jin Pen
    • Cheng Luo
    • Yuan-Yuan Zhang
    • Guang-Ming Li
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, P.R. China, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
    Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 305
    |
    Published online on: February 26, 2021
       https://doi.org/10.3892/mmr.2021.11944
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Abstract

Hepatic fibrosis, a common pathological manifestation of chronic liver injury, is generally considered to be the end result of an increase in extracellular matrix produced by activated hepatic stellate cells (HSCs). The aim of the present study was to target the mechanisms underlying HSC activation in order to provide a powerful therapeutic strategy for the prevention and treatment of liver fibrosis. In the present study, a high‑throughput screening assay was established, and the histone deacetylase inhibitor givinostat was identified as a potent inhibitor of HSC activation in vitro. Givinostat significantly inhibited HSC activation in vivo, ameliorated carbon tetrachloride‑induced mouse liver fibrosis and lowered plasma aminotransferases. Transcriptomic analysis revealed the most significantly regulated genes in the givinostat treatment group in comparison with those in the solvent group, among which, dermokine (Dmkn), mesothelin (Msln) and uroplakin‑3b (Upk3b) were identified as potential regulators of HSC activation. Givinostat significantly reduced the mRNA expression of Dmkn, Msln and Upk3b in both a mouse liver fibrosis model and in HSC‑LX2 cells. Knockdown of any of the aforementioned genes inhibited the TGF‑β1‑induced expression of α‑smooth muscle actin and collagen type I, indicating that they are crucial for HSC activation. In summary, using a novel strategy targeting HSC activation, the present study identified a potential epigenetic drug for the treatment of hepatic fibrosis and revealed novel regulators of HSC activation.
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Copy and paste a formatted citation
Spandidos Publications style
Huang H, Zhou X, Liu Y, Fan S, Liao L, Huang J, Shi C, Yu L, Pen J, Luo C, Luo C, et al: Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation. Mol Med Rep 23: 305, 2021.
APA
Huang, H., Zhou, X., Liu, Y., Fan, S., Liao, L., Huang, J. ... Li, G. (2021). Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation. Molecular Medicine Reports, 23, 305. https://doi.org/10.3892/mmr.2021.11944
MLA
Huang, H., Zhou, X., Liu, Y., Fan, S., Liao, L., Huang, J., Shi, C., Yu, L., Pen, J., Luo, C., Zhang, Y., Li, G."Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation". Molecular Medicine Reports 23.5 (2021): 305.
Chicago
Huang, H., Zhou, X., Liu, Y., Fan, S., Liao, L., Huang, J., Shi, C., Yu, L., Pen, J., Luo, C., Zhang, Y., Li, G."Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation". Molecular Medicine Reports 23, no. 5 (2021): 305. https://doi.org/10.3892/mmr.2021.11944
Copy and paste a formatted citation
x
Spandidos Publications style
Huang H, Zhou X, Liu Y, Fan S, Liao L, Huang J, Shi C, Yu L, Pen J, Luo C, Luo C, et al: Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation. Mol Med Rep 23: 305, 2021.
APA
Huang, H., Zhou, X., Liu, Y., Fan, S., Liao, L., Huang, J. ... Li, G. (2021). Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation. Molecular Medicine Reports, 23, 305. https://doi.org/10.3892/mmr.2021.11944
MLA
Huang, H., Zhou, X., Liu, Y., Fan, S., Liao, L., Huang, J., Shi, C., Yu, L., Pen, J., Luo, C., Zhang, Y., Li, G."Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation". Molecular Medicine Reports 23.5 (2021): 305.
Chicago
Huang, H., Zhou, X., Liu, Y., Fan, S., Liao, L., Huang, J., Shi, C., Yu, L., Pen, J., Luo, C., Zhang, Y., Li, G."Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation". Molecular Medicine Reports 23, no. 5 (2021): 305. https://doi.org/10.3892/mmr.2021.11944
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