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Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis.

Publication ,  Journal Article
Jian, C; Fu, J; Cheng, X; Shen, L-J; Ji, Y-X; Wang, X; Pan, S; Tian, H; Tian, S; Liao, R; Song, K; Wang, H-P; Zhang, X; Wang, Y; Huang, Z ...
Published in: Cell Metab
May 5, 2020

Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC despite its serious adverse effects. Here, we report that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib's benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP-activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug's current use in HCC.

Duke Scholars

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Published In

Cell Metab

DOI

EISSN

1932-7420

Publication Date

May 5, 2020

Volume

31

Issue

5

Start / End Page

892 / 908.e11

Location

United States

Related Subject Headings

  • Sorafenib
  • Non-alcoholic Fatty Liver Disease
  • Mitochondria
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Liver Neoplasms
  • Humans
  • Endocrinology & Metabolism
  • Dose-Response Relationship, Drug
 

Citation

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Jian, C., Fu, J., Cheng, X., Shen, L.-J., Ji, Y.-X., Wang, X., … Li, H. (2020). Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis. Cell Metab, 31(5), 892-908.e11. https://doi.org/10.1016/j.cmet.2020.04.011
Jian, Chongshu, Jiajun Fu, Xu Cheng, Li-Jun Shen, Yan-Xiao Ji, Xiaoming Wang, Shan Pan, et al. “Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis.Cell Metab 31, no. 5 (May 5, 2020): 892-908.e11. https://doi.org/10.1016/j.cmet.2020.04.011.
Jian C, Fu J, Cheng X, Shen L-J, Ji Y-X, Wang X, et al. Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis. Cell Metab. 2020 May 5;31(5):892-908.e11.
Jian, Chongshu, et al. “Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis.Cell Metab, vol. 31, no. 5, May 2020, pp. 892-908.e11. Pubmed, doi:10.1016/j.cmet.2020.04.011.
Jian C, Fu J, Cheng X, Shen L-J, Ji Y-X, Wang X, Pan S, Tian H, Tian S, Liao R, Song K, Wang H-P, Zhang X, Wang Y, Huang Z, She Z-G, Zhang X-J, Zhu L, Li H. Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis. Cell Metab. 2020 May 5;31(5):892-908.e11.
Journal cover image

Published In

Cell Metab

DOI

EISSN

1932-7420

Publication Date

May 5, 2020

Volume

31

Issue

5

Start / End Page

892 / 908.e11

Location

United States

Related Subject Headings

  • Sorafenib
  • Non-alcoholic Fatty Liver Disease
  • Mitochondria
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Liver Neoplasms
  • Humans
  • Endocrinology & Metabolism
  • Dose-Response Relationship, Drug