2. Academic Validation
  3. Discovery of 3,7-dimethoxyflavone that inhibits liver fibrosis based on dual mechanisms of antioxidant and inhibitor of activated hepatic stellate cell

Discovery of 3,7-dimethoxyflavone that inhibits liver fibrosis based on dual mechanisms of antioxidant and inhibitor of activated hepatic stellate cell

  • Free Radic Biol Med. 2023 Aug 1;204:195-206. doi: 10.1016/j.freeradbiomed.2023.05.001.
Hyomin Park 1,  Eun Ju Lee 2,  Dodam Moon 3,  Hyunji Yun 4,  Areum Cha 5,  Injoo Hwang 6,  Hyo-Soo Kim 7
Affiliations

Affiliations

  • 1 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. Electronic address: [email protected].
  • 2 Interdisciplinary Program in Stem Cell Biology, Seoul National University of Medicine, Seoul, 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. Electronic address: [email protected].
  • 3 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. Electronic address: [email protected].
  • 4 Interdisciplinary Program in Stem Cell Biology, Seoul National University of Medicine, Seoul, 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. Electronic address: [email protected].
  • 5 Interdisciplinary Program in Stem Cell Biology, Seoul National University of Medicine, Seoul, 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. Electronic address: [email protected].
  • 6 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. Electronic address: [email protected].
  • 7 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea; Interdisciplinary Program in Stem Cell Biology, Seoul National University of Medicine, Seoul, 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. Electronic address: [email protected].
PMID: 37146699 DOI: 10.1016/j.freeradbiomed.2023.05.001
Abstract

The important pathway toward liver fibrosis is the TGF-β1-induced activation of hepatic stellate cells (HSCs). To discover chemicals to inhibit liver fibrosis, we screened 3000 chemicals using cell array system where human HSCs line LX2 cells are activated with TGF-β1. We discovered 3,7-dimethoxyflavone (3,7-DMF) as a chemical to inhibit TGF-β1-induced activation of HSCs. In the thioacetamide (TAA)-induced mouse liver fibrosis model, 3,7-DMF treatment via intraperitoneal or oral administration prevented liver fibrosis as well as reversed the established fibrosis in the separate experiments. It also reduced liver Enzyme elevation, suggesting protective effect on hepatocytes because it has antioxidant effect. Treatment with 3,7-DMF induced antioxidant genes, quenches ROS away, and improved the hepatocyte condition that was impaired by H2O2 as reflected by restoration of HNF-4α and albumin. In the TAA-mouse liver injury model also, TAA significantly increased ROS in the liver which led to decrease of albumin and nuclear expression of HNF-4α, increase of TGF-β1 and hepatocytes death, accumulation of lipid, and extra-nuclear localization of HMGB1. Treatment of 3,7-DMF normalized all these pathologic findings and prevented or resolved liver fibrosis. In conclusion, we discovered 3,7-DMF that inhibits liver fibrosis based on dual actions; antioxidant and inhibitor of TGF-β1-induced activation of HSCs.

Keywords

3,7-Dimethoxyflavone; Hepatocyte; Liver fibrosis; Oral administration; Oxidative stress; Reactive oxygen species.

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