Thursday, April 3, 2025
4/3/2025
Oral digoxin for the treatment of NASH - 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 RORγt 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).