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组蛋白去乙酰化酶抑制剂 givinostat 通过调节肝星状细胞活化缓解肝纤维化。

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

机构信息

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.

出版信息

Mol Med Rep. 2021 May;23(5). doi: 10.3892/mmr.2021.11944. Epub 2021 Mar 2.

DOI:10.3892/mmr.2021.11944
PMID:33649839
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7974418/
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 . Givinostat significantly inhibited HSC activation , 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 , and 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.

摘要

肝纤维化是慢性肝损伤的常见病理表现，一般被认为是活化的肝星状细胞（HSCs）产生的细胞外基质增加的最终结果。本研究旨在针对 HSC 活化的机制，为预防和治疗肝纤维化提供一种强大的治疗策略。在本研究中，建立了一种高通量筛选测定法，并鉴定组蛋白去乙酰化酶抑制剂 Givinostat 是一种有效的 HSC 活化抑制剂。Givinostat 显著抑制 HSC 活化，改善四氯化碳诱导的小鼠肝纤维化并降低血浆氨基转移酶。转录组分析显示，与溶剂组相比，Givinostat 治疗组中最显著调节的基因，其中，真皮素（Dmkn）、间皮素（Msln）和尿路上皮蛋白 3b（Upk3b）被鉴定为 HSC 活化的潜在调节剂。Givinostat 显著降低了小鼠肝纤维化模型和 HSC-LX2 细胞中 、 和 的 mRNA 表达。敲低上述任何一种基因均抑制 TGF-β1 诱导的α-平滑肌肌动蛋白和 I 型胶原的表达，表明它们对 HSC 活化至关重要。总之，本研究采用一种针对 HSC 活化的新策略，鉴定了一种治疗肝纤维化的潜在表观遗传药物，并揭示了 HSC 活化的新调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/674f238ead26/mmr-23-05-11944-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/1640334169b4/mmr-23-05-11944-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/9ad77bf24351/mmr-23-05-11944-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/414678c258e1/mmr-23-05-11944-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/d81a9acef965/mmr-23-05-11944-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/674f238ead26/mmr-23-05-11944-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/1640334169b4/mmr-23-05-11944-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/9ad77bf24351/mmr-23-05-11944-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/414678c258e1/mmr-23-05-11944-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/d81a9acef965/mmr-23-05-11944-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ac/7974418/674f238ead26/mmr-23-05-11944-g04.jpg

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