Computational repositioning of dimethyl fumarate for treating alcoholic liver disease.
Ye ZhangShuang ZhaoYing FuLu YanYilu FengYaqi ChenYijia WuYalan DengGuiying ZhangZhuchu ChenYongheng ChenTing LiuPublished in: Cell death & disease (2020)
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.
Keyphrases
- oxidative stress
- induced apoptosis
- drug induced
- liver injury
- nuclear factor
- reactive oxygen species
- drug administration
- cell cycle arrest
- cell death
- toll like receptor
- dna damage
- diabetic rats
- signaling pathway
- endoplasmic reticulum stress
- genome wide
- insulin resistance
- early onset
- amino acid
- gene expression
- climate change
- type diabetes
- dna methylation
- risk assessment
- immune response
- adverse drug
- protein kinase
- high fat diet induced
- human health
- metabolic syndrome
- binding protein