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

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. [Display omitted] •Low-dose sorafenib safely suppresses NASH progression in mice•Low-dose sorafenib resolves NASH in monkeys without detectable toxicities•AMPK activation is required for the therapeutic effects of sorafenib in NASH•Sorafenib activates AMPK by acting as a mitochondrial uncoupler Jian et al. show that low-dose sorafenib safely and effectively suppressed NASH progression in both mice and monkeys. Mechanistically, induction of mitochondrial uncoupling and subsequent AMPK activation primarily underlies the therapeutic effects of sorafenib in NASH.