A novel STAT3 inhibitor, STX-0119, attenuates liver fibrosis by inactivating hepatic stellate cells in mice
- Authors
- Choi, Seungho; Jung, Hyun Jin; Kim, Min Woo; Kang, Ju-Hee; Shin, Dongyun; Jang, Yeong-Su; Yoon, Yeo Sung; Oh, Seung Hyun
- Issue Date
- 21-May-2019
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE
- Keywords
- Liver fibrosis; Cirrhosis; Hepatic stellate cell; STAT3; STX-0119
- Citation
- BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.513, no.1, pp.49 - 55
- Journal Title
- BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
- Volume
- 513
- Number
- 1
- Start Page
- 49
- End Page
- 55
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/1477
- DOI
- 10.1016/j.bbrc.2019.03.156
- ISSN
- 0006-291X
- Abstract
- Liver fibrosis is characterized by formation of scar tissue in the liver. The role of STAT3 signaling has been implicated on activating hepatic stellate cells (HSC) to myofibroblast-like cells in liver fibrosis. Major factors that activate STAT3 signaling are TGF-beta 1 and IL-6, which are upregulated in the liver in patients afflicted with liver fibrosis. Recent reports indicate that not only IL-6, but also the non-canonical signaling pathway of TGF-beta 1 is associated with STAT3 signaling. In this study, we demonstrate a new function of the STAT3 inhibitor, STX-0119, in liver fibrosis. STX-0119 is an inhibitor of STAT3 dimerization, which is required for nuclear localization of STAT3. We first investigated the anti-fibrotic effect of STX-0119 in in vitro experiments. Exposure to STX-0119 inhibited the nuclear localization of STAT3 in HSC5, resulting in decreased expression of its target genes, such as collal and alpha SMA. In addition, STX-0119 also inhibited the TGF-beta 1/1-6-induced activation of HSCs. Next, we examined the in vivo effect of STX-0119 in the liver fibrosis mouse model using thioacetamide (TAA) and carbon tetrachloride (CCL4). STX-0119 attenuated the TAA-induced liver fibrosis by inhibiting activation of HSC5 to myofibroblast-like cells. Consistent with the in vivo results using TAA-induced liver fibrosis model, treatment of STX-0119 similarly attenuated CCl4-induced liver fibrosis. In conclusion, we believe that STX-0119 inhibits the development of liver fibrosis by blocking the activation of hepatic stellate cells. These results indicate that STX-0119 is a potential new therapeutic strategy to prevent disease progression to cirrhosis. (C) 2019 Elsevier Inc. All rights reserved.
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