PMID- 32811823 OWN - NLM STAT- MEDLINE DCOM- 20210412 LR - 20220418 IS - 2041-4889 (Electronic) VI - 11 IP - 8 DP - 2020 Aug 18 TI - Computational repositioning of dimethyl fumarate for treating alcoholic liver disease. PG - 641 LID - 10.1038/s41419-020-02890-3 [doi] LID - 641 AB - 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. FAU - Zhang, Ye AU - Zhang Y AD - Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Center for Geriatrics Clinical Research, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. FAU - Zhao, Shuang AU - Zhao S AD - Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Center for Geriatrics Clinical Research, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. FAU - Fu, Ying AU - Fu Y AD - Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Center for Geriatrics Clinical Research, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. FAU - Yan, Lu AU - Yan L AD - Department of Gastroenterology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. FAU - Feng, Yilu AU - Feng Y AUID- ORCID: 0000-0001-8418-4561 AD - Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Center for Geriatrics Clinical Research, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. FAU - Chen, Yaqi AU - Chen Y AD - Department of Gastroenterology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. FAU - Wu, Yijia AU - Wu Y AD - Department of Gastroenterology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. FAU - Deng, Yalan AU - Deng Y AD - Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Center for Geriatrics Clinical Research, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. AD - Department of Gastroenterology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. FAU - Zhang, Guiying AU - Zhang G AD - Department of Gastroenterology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. FAU - Chen, Zhuchu AU - Chen Z AD - Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Center for Geriatrics Clinical Research, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. FAU - Chen, Yongheng AU - Chen Y AUID- ORCID: 0000-0001-8139-6892 AD - Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Center for Geriatrics Clinical Research, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. yonghenc@163.com. FAU - Liu, Ting AU - Liu T AD - Department of Gastroenterology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. liuting818@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200818 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Immunosuppressive Agents) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - 0 (Reactive Oxygen Species) RN - FO2303MNI2 (Dimethyl Fumarate) SB - IM MH - Animals MH - China MH - Computational Biology/methods MH - Dimethyl Fumarate/chemistry/*pharmacology MH - Disease Models, Animal MH - Drug Repositioning/methods MH - Hep G2 Cells MH - Humans MH - Immunosuppressive Agents/metabolism MH - Liver/metabolism MH - Liver Diseases, Alcoholic/*metabolism/*therapy MH - Male MH - Mice MH - Mice, Inbred C57BL MH - NF-E2-Related Factor 2/genetics/metabolism MH - Oxidative Stress/drug effects MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/drug effects PMC - PMC7434920 COIS- The authors declare that they have no conflict of interest. EDAT- 2020/08/20 06:00 MHDA- 2021/04/13 06:00 PMCR- 2020/08/18 CRDT- 2020/08/20 06:00 PHST- 2020/01/04 00:00 [received] PHST- 2020/08/05 00:00 [accepted] PHST- 2020/08/04 00:00 [revised] PHST- 2020/08/20 06:00 [entrez] PHST- 2020/08/20 06:00 [pubmed] PHST- 2021/04/13 06:00 [medline] PHST- 2020/08/18 00:00 [pmc-release] AID - 10.1038/s41419-020-02890-3 [pii] AID - 2890 [pii] AID - 10.1038/s41419-020-02890-3 [doi] PST - epublish SO - Cell Death Dis. 2020 Aug 18;11(8):641. doi: 10.1038/s41419-020-02890-3.