BACKGROUND/AIMS: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1α activates hepatic stellate cells (HSCs) and increases transforming growth factor-β (TGF-β) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197, on HIF1α-derived TGF-β signaling in cholestatic liver fibrosis. METHODS: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1α-derived TGF-β signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. RESULTS: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1α-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1α-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. CONCLUSION: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1α-induced TGF-β signaling.
BACKGROUND/AIMS: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1α activates hepatic stellate cells (HSCs) and increases transforming growth factor-β (TGF-β) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197, on HIF1α-derived TGF-β signaling in cholestatic liver fibrosis. METHODS: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1α-derived TGF-β signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. RESULTS: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1α-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1α-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. CONCLUSION: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1α-induced TGF-β signaling.
Authors: Joseph Carpenter; Gang Wu; Ying Wang; Erica M Cook; Tao Wang; Doree Sitkoff; Karen A Rossi; Kathy Mosure; Xiaoliang Zhuo; Gary G Cao; Milinda Ziegler; Anthony V Azzara; Jack Krupinski; Matthew G Soars; Bruce Alan Ellsworth; Dean A Wacker Journal: ACS Med Chem Lett Date: 2021-08-05 Impact factor: 4.632
Authors: Qingshan Chen; Hai Zhang; Yan Cao; Ying Li; Sen Sun; Junping Zhang; Guoqing Zhang Journal: Drug Des Devel Ther Date: 2017-07-26 Impact factor: 4.162
Authors: Danielle Brooks; Alexandra Zimmer; Lalage Wakefield; L Tiffany Lyle; Simone Difilippantonio; Fabio C Tucci; Stephane Illiano; Christina M Annunziata; Patricia S Steeg Journal: Oncotarget Date: 2018-05-04