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

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Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis.
Cell Metabolism ( IF 27.7 ) Pub Date : 2020-05-05 , 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 ₁ , Lihua Zhu ₁ , Hongliang Li ₉

Affiliation

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Institute of Model Animal of Wuhan University, Wuhan 430071, China.
Institute of Model Animal of Wuhan University, Wuhan 430071, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Institute of Model Animal of Wuhan University, Wuhan 430071, China; School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Institute of Model Animal of Wuhan University, Wuhan 430071, China; College of Life Sciences, Wuhan University, Wuhan 430072, China.
Department of Anesthesiology, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
College of Life Sciences, Wuhan University, Wuhan 430072, China.
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.

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.

中文翻译：

低剂量索拉非尼充当线粒体解偶联剂并改善非酒精性脂肪性肝炎。

非酒精性脂肪性肝炎 (NASH) 正在成为肝细胞癌 (HCC) 的主要原因之一。尽管有严重的不良反应，但索拉非尼是晚期 HCC 的唯一一线治疗药物。在这里，我们报告说，在相当于 HCC 临床剂量的大约十分之一时，索拉非尼治疗有效地阻止了小鼠和猴子的 NASH 进展，而没有观察到任何明显的不良事件。从机制上讲，索拉非尼在 NASH 中的益处与其在 HCC 中的经典激酶靶标无关，但涉及诱导轻度线粒体解偶联和随后激活 AMP 活化蛋白激酶 (AMPK)。总的来说，我们的研究结果证明了在 NASH 中低剂量索拉非尼治疗的先前未被认可的治疗效果和信号传导机制。

更新日期：2020-05-05

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