2. Academic Validation
  3. Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis

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

  • Cell Metab. 2020 May 5;31(5):892-908.e11. doi: 10.1016/j.cmet.2020.04.011.
Chongshu Jian 1,  Jiajun Fu 2,  Xu Cheng 1,  Li-Jun Shen 1,  Yan-Xiao Ji 2,  Xiaoming Wang 3,  Shan Pan 1,  Han Tian 1,  Song Tian 1,  Rufang Liao 4,  Kehan Song 5,  Hai-Ping Wang 1,  Xin Zhang 6,  Yibin Wang 7,  Zan Huang 8,  Zhi-Gang She 1,  Xiao-Jing Zhang 9,  Lihua Zhu 10,  Hongliang Li 11
Affiliations

Affiliations

  • 1 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Institute of Model Animal of Wuhan University, Wuhan 430071, China.
  • 2 Institute of Model Animal of Wuhan University, Wuhan 430071, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • 3 Institute of Model Animal of Wuhan University, Wuhan 430071, China; School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 4 Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • 5 Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 6 Institute of Model Animal of Wuhan University, Wuhan 430071, China; College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 7 Department of Anesthesiology, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
  • 8 College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 9 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Institute of Model Animal of Wuhan University, Wuhan 430071, China. Electronic address: zhangxjing@whu.edu.cn.
  • 10 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Institute of Model Animal of Wuhan University, Wuhan 430071, China. Electronic address: zhulh@whu.edu.cn.
  • 11 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Institute of Model Animal of Wuhan University, Wuhan 430071, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: lihl@whu.edu.cn.
PMID: 32375062 DOI: 10.1016/j.cmet.2020.04.011
Abstract

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.

Keywords

AMP–activated protein kinase (AMPK); mitochondrial uncoupler; nonalcoholic steatohepatitis (NASH); sorafenib.

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