# Inhibition of Sterile Inflammation by Digoxin in Alcoholic Hepatitis

> **NIH NIH U01** · YALE UNIVERSITY · 2020 · $241,342

## Abstract

ABSTRACT: Alcoholic hepatitis (AH) is a major liver disease, and has an inpatient mortality of between 25-40%.
Liver inflammation is a key feature of AH, yet the factors which drive this inflammatory response are not known.
We have identified novel key drivers of liver inflammation which are the subject of this application. We have also
identified novel proteomic and molecular markers in AH which will be used to predict prognosis.
 We have shown that activation of the nuclear (hypoxia inhibitory factor 1-α: HIF-1α) pathway was required
for the development of sustained sterile inflammation, which suggested that inhibition of HIF-1α may be
therapeutic in AH[1]. In a high throughput screen cardiac glycoside were identified to have significant ability to
inhibit HIF-1α[2]. The preliminary data demonstrates i) Up-regulation of HIF-1α dependent genes in liver tissues
from early AH, as compared to severe AH, from the InTeam consortium ii) Ability of digoxin to reduce tissue
damage in a model of alcohol, and others forms of liver injury. iii) Digoxin binds to the enzyme pyruvate kinase
M2 (PKM2), iv) Digoxin reduces PKM2 binding to the HIF-1α promoter and limits up-regulation of HIF-1α, and
HIF-1α response genes. v) An aptamer based proteomic analysis of serum shows that in patients with the AH
and the systemic inflammatory response (SIRS) there is an increase in tumor necrosis factor related proteins,
low affinity immunoglobulin gamma Fc region receptor II, complement components, kallikrein and fibroblast
growth factors. vi) Serum DNA is known to be a pro-inflammatory ligand and serum DNA levels correlated with
peripheral blood white cell count in AH.
Aim 1. Obtain clinical data supporting the therapeutic use of digoxin in alcoholic hepatitis.
Aim 2. Identify dominant and novel targets that are regulated by PKM2 in alcoholic hepatitis.
Aim 3. Obtain plasma proteomic and molecular data to allow for early identification of patients with SIRS.
Collectively this will allow us to obtain the necessary data towards clinically testing low dose digoxin in AH. In
addition, it will allow us to identify novel protein markers and pro-inflammatory signals in the serum of patients
with AH. Finally, we will be able to identify if any of the novel protein markers are associated with the novel PKM2
pathway we have identified.

## Key facts

- **NIH application ID:** 9983532
- **Project number:** 5U01AA026962-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** WAJAHAT Zafar MEHAL
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $241,342
- **Award type:** 5
- **Project period:** 2018-09-22 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983532

## Citation

> US National Institutes of Health, RePORTER application 9983532, Inhibition of Sterile Inflammation by Digoxin in Alcoholic Hepatitis (5U01AA026962-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9983532. Licensed CC0.

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