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

doi:10.3892/mmr.2021.11944

KMS@SIMM > 新药研究国家重点实验室

	Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation
	Huang, He-Ming 1,2; Zhou, Xiao-Ru 2; Liu, Yan-Jun 1,2; Fan, Shi-Jie 2,3; Liao, Li-Ping 2,3; Huang, Jing 2,3; Shi, Cui-Cui 1; Yu, Liang2 ; Pen, Jin-Jin 1,2; Luo, Cheng2,3 ; Zhang, Yuan-Yuan 2; Li, Guang-Ming 1
	2021-05-01
发表期刊	MOLECULAR MEDICINE REPORTS (IF:1.922[JCR-2017],1.912[5-Year])
ISSN	1791-2997
卷号	23 期号:5 页码:12
摘要	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-beta 1-induced expression of alpha-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.
关键词	liver fibrosis hepatic stellate cell histone deacetylase inhibitor epigenetics givinostat
DOI	10.3892/mmr.2021.11944
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China[81070344] ; National Natural Science Foundation of China[81803554] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[81773568] ; Ministry of Science and Technology of China[2015CB910304] ; National Science & Technology Major Project of China[2018ZX09711002] ; Youth Innovation Promotion Association[2017333]
WOS研究方向	Oncology ; Research & Experimental Medicine
WOS类目	Oncology ; Medicine, Research & Experimental
WOS记录号	WOS:000631108000001
出版者	SPANDIDOS PUBL LTD
引用统计	被引频次：9[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.183/handle/2S10ELR8/295550
专题	新药研究国家重点实验室
通讯作者	Shi, Cui-Cui; Li, Guang-Ming
作者单位	1.Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Gastroenterol, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Chem Biol Ctr, Beijing 100049, Peoples R China
第一作者单位	药物发现与设计中心
推荐引用方式 GB/T 7714	Huang, He-Ming,Zhou, Xiao-Ru,Liu, Yan-Jun,et al. Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation[J]. MOLECULAR MEDICINE REPORTS,2021,23(5):12.
APA	Huang, He-Ming.,Zhou, Xiao-Ru.,Liu, Yan-Jun.,Fan, Shi-Jie.,Liao, Li-Ping.,...&Li, Guang-Ming.(2021).Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation.MOLECULAR MEDICINE REPORTS,23(5),12.
MLA	Huang, He-Ming,et al."Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation".MOLECULAR MEDICINE REPORTS 23.5(2021):12.