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

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.

• Authors: Guifang Du, Jing Wang, Ting Zhang, Qiang Ding, Xiaodong Jia, Xueke Zhao, Jinke Dong, Xinrui Yang, Shanshan Lu, Cuihong Zhang, Ze Liu, Zhen Zeng, Rifaat Safadi, Ruizhao Qi, Xin Zhao, Zhixian Hong, Yinying Lu
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 2 Pg. 118 (02 12 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 32051399 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzodioxoles
• Protein Kinase Inhibitors
• Quinazolines
• saracatinib
• Carbon Tetrachloride
• FYN protein, human
• Fyn protein, mouse
• Fyn protein, rat
• Proto-Oncogene Proteins c-fyn

Topics

• Animals
• Benzodioxoles (pharmacology)
• Carbon Tetrachloride
• Case-Control Studies
• Cell Line
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chemical and Drug Induced Liver Injury (enzymology, etiology, pathology, prevention & control)
• Hepatic Stellate Cells (drug effects, enzymology, pathology)
• Humans
• Liver (drug effects, enzymology, pathology)
• Liver Cirrhosis, Experimental (chemically induced, enzymology, pathology, prevention & control)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-fyn (antagonists & inhibitors, genetics, metabolism)
• Quinazolines (pharmacology)
• Rats
• Signal Transduction