Targeting Src family kinase member Fyn by Saracatinib attenuated liver fibrosis in vitro and in vivo

Guifang Du,Rifaat Safadi,Jinke Dong,Xueke Zhao,Xinrui Yang,Cuihong Zhang,Yinying Lu,Zhen Zeng,Qiang Ding,Shanshan Lu,Ting Zhang,Xin Zhao,Ruizhao Qi,Ze Liu,Jing Wang,Xiaodong Jia,Zhixian Hong

doi:10.1038/s41419-020-2229-2

Abstract

Recent studies suggest that Src family kinase (SFK) plays important roles in systemic sclerosis and pulmonary fibrosis. However, how SFKs contributed to the pathogenesis of liver fibrosis remains largely unknown. Here, we investigated the role of Fyn, a member of SFK, in hepatic stellate cell (HSC) activation and liver fibrosis, and evaluated the anti-fibrotic effects of Saracatinib, a clinically proven safe Fyn inhibitor. Fyn activation was examined in human normal and fibrotic liver tissues. The roles of Fyn in HSC activation and liver fibrosis were evaluated in HSC cell lines by using Fyn siRNA and in Fyn knockout mice. The effects of Saracatinib on HSC activation and liver fibrosis were determined in primary HSCs and CCl4 induced liver fibrosis model. We showed that the Fyn was activated in the liver of human fibrosis patients. TGF-β induced the activation of Fyn in HSC cell lines. Knockdown of Fyn significantly blocked HSC activation, proliferation, and migration. Fyn deficient mice were resistant to CCl4 induced liver fibrosis. Saracatinib treatment abolished the activation of Fyn, downregulated the Fyn/FAK/N-WASP signaling in HSCs, and subsequently prevented the activation of HSCs. Saracatinib treatment significantly reduced the severity liver fibrosis induced by CCl4 in mice. In conclusions, our findings supported the critical role of Fyn in HSC activation and development of liver fibrosis. Fyn could serve as a promising drug target for liver fibrosis treatment. Fyn inhibitor Saracatinib significantly inhibited HSC activation and attenuated liver fibrosis in mouse model.

Highlights

Liver fibrosis is a global health problem and a critical process in liver diseases as well as a major risk factor for progression to cirrhosis and hepatocellular carcinoma[1]
We investigated the role of Fyn, one of the Src family kinase (SFK) which is highly expressed in hepatic stellate cell (HSC) and activated in fibrotic livers, in the development of liver fibrosis
Fyn was abnormally activated in clinic fibrotic liver tissues To determine the role of SFKs in the development of liver fibrosis, we treated human HSC cell line LX-2 cells with profibrogenic cytokine TGF-β (10 ng/ml)

Summary

Introduction

Liver fibrosis is a global health problem and a critical process in liver diseases as well as a major risk factor for progression to cirrhosis and hepatocellular carcinoma[1]. Chronic hepatocyte death (HSCs) play a pivotal role in the development of liver fibrosis. In response to liver damage, HSCs undergo a process of activation that acquires a myofibroblast-like phenotype with increased cell proliferation, the synthesis of excess extracellular matrix (ECM), the secretion of proinflammatory cytokines, and the capacity to migrate and contract[4]. Several cytokines are critical in HSC activation, one of the most important cytokine is TGF-β3. TGF-β induces the activation of the downstream molecules such as SMAD, ERK, AKT signaling and Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion