Project Summary/ Abstract
Nonalcoholic steatohepatitis (NASH) has reached epidemic proportions and will result in an immense
burden of chronic liver disease and cirrhosis. Therapeutics for NASH is a very active area of investigation, but
even with development of propriety drugs there will be major issues of financial availability for such a large
percentage of the population. This motivated us to search for generic drugs with therapeutic potential in NASH,
resulting in the identification of digoxin. We, and others, have identified an important role of digoxin in providing
hepatoprotection in a range of liver conditions, including NASH. We have further identified that digoxin binds to
pyruvate kinase M2 (PKM2) and stops PKM2 from initiating immune responses in macrophages. There is a
large amount of published data from other studies that supports the ability of digoxin to reduce inflammation,
steatosis, and fibrosis in the liver. There is also a high likelihood for translation of these findings to humans
because we have demonstrated that oral digoxin reduces immune responses in healthy volunteers and others
have demonstrated that oral digoxin reduces serum cholesterol, as we previously reported based on
observations in mice.
At least three mechanisms of digoxin-induced hepatoprotection have been identified. These include binding
to PKM2 as reported by us, digoxin-mediated inhibition of ROR¿t and TH17 cells, as well as activation of
transcription factor EB (TFEB). Of great clinical relevance is the fact that hepatoprotection occurs at a
concentration below that required for cardiac effects, significantly improving the safety profile of digoxin.
The large amount of experimental and translational data on the anti-inflammatory and hepatoprotective
effects of digoxin which has accumulated over the last 55 years now supports the conduct of a clinical trial to
directly test the ability of digoxin as a therapy for NASH. We will test the ability of oral digoxin to reduce
steatosis, inflammation, and fibrosis in patients with NASH. This will be done at the standard cardiac dose and
at a lower dose. In addition, we will examine the immunomodulatory effects of digoxin with respect to myeloid
cells, TH17 cells, and liver tissue and correlate these with the clinical response. The demonstration of
hepatoprotective effects of a generic medication for NASH will be transformative. Due to the lack of commercial
return, this avenue of research will only occur outside the pharmaceutical industry.