Abstract
Alcoholic liver disease (ALD) is a chronic alcohol-induced disorder of the liver for which there are few effective therapies for severe forms of ALD and for those who do not achieve alcohol abstinence. In this study, we used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene-expression profiles to identify candidate U.S. Food and Drug Administration (FDA)–approved drugs to treat ALD. One of the top compounds predicted to be therapeutic for ALD by our approach was dimethyl fumarate (DMF), an nuclear factor erythroid 2-related factor 2 (NRF2) inducer. We experimentally validated DMF in liver cells and in vivo. Our work demonstrates that DMF is able to significantly upregulate the NRF2 protein level, increase NRF2 phosphorylation, and promote NRF2 nuclear localization in liver cells. DMF also reduced the reactive oxygen species (ROS) level, lipid peroxidation, and ferroptosis. Furthermore, DMF treatment could prevent ethanol-induced liver injury in ALD mice. Our results provide evidence that DMF might serve as a therapeutic option for ALD in humans, and support the use of computational repositioning to discover therapeutic options for ALD.
Highlights
Oxidative stress is implicated in the development of diverse liver disorders, such as alcoholic liver disease (ALD)[1,2]
Among nuclear factor erythroid 2-related factor 2 (NRF2)-compound interactions, the main use of Dimethyl fumarate (DMF) is previously tested with some success in multiple sclerosis patients with relapsing forms, suggesting that DMF used in the clinic may affect the ALD gene-expression signature
DMF ameliorated the hepatic steatosis induced by ethanol, as observed in liver sections stained with hematoxylin and eosin (H&E) (Fig. 1b and Supplementary Fig. S1A)
Summary
Oxidative stress is implicated in the development of diverse liver disorders, such as alcoholic liver disease (ALD)[1,2]. Official journal of the Cell Death Differentiation Association enabled the development of drug repurposing to identify novel treatment options for ALD. NRF2 is a basic leucine zipper (bZIP) transcription factor that regulates the expression of certain proteins, which protect cells against oxidative stress. We found that the FDA-approved NRF2 inducer[9], dimethyl fumarate (DMF), which has not previously been described to have a therapeutic association with ALD, was determined to have a strong therapeutic potential for repositioning in ALD. We evaluated the efficacy of DMF for ALD in liver cells and in vivo, using an ethanol-induced mouse model. Concordant with our computational prediction, the experimental results demonstrate that DMF is able to significantly ameliorate ethanol-induced liver injury compared to untreated groups
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