Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis

He-ming Huang1,2, Shi-jie Fan2,3, Xiao-ru Zhou2, Yan-jun Liu1,2, Xiao Li2,3, Li-ping Liao2,3, Jing Huang2,3, Cui-cui Shi1, Liang Yu2, Rong Fu1,2, Jian-gao Fan1, Yuan-yuan Zhang2, Cheng Luo2,3, Guang-ming Li1
1 Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China
2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3 University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Yuan-yuan Zhang:, Cheng Luo:, Guang-ming Li:,
DOI: 10.1038/s41401-021-00725-1
Received: 3 October 2020
Accepted: 22 June 2021
Advance online: 2 August 2021


Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we evaluated the therapeutic potential of givinostat, a histone deacetylase (HDAC) inhibitor, in the treatment of NASH in vivo and in vitro. Liver inflammation was induced in mice by feeding a methionine- and choline-deficient diet (MCD) or a fructose, palmitate, cholesterol diet (FPC). The mice were treated with givoinostat (10 mg·kg−1·d−1, ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.

Keywords: nonalcoholic steatohepatitis; inflammation; histone deacetylase inhibitor; givinostat; epigenetics

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