BRD4 is a novel therapeutic target for liver fibrosis
Open accessAbstract
Significance: Liver fibrosis and cirrhosis are chronic liver diseases, resulting in life-threatening conditions with no FDA-approved therapy. Here, we identify bromodomain-containing protein 4 (BRD4) as a critical regulator for enhancer-mediated profibrotic gene expression in hepatic stellate cells (HSCs). In support of this notion, we find BRD4-loaded enhancers are associated with multiple profibrotic pathways in HSCs and that pharmacological inhibition of BRD4 blocks HSC activation into myofibroblasts. Furthermore, small molecule inhibitors of BRD4 are not only protective against, but can limit the fibrotic response in CCl 4 -induced fibrosis in a mouse model. Thus, our studies implicate BRD4 as a global genomic regulator of the fibrotic gene regulatory network and suggest bromodomains as potential therapeutic targets to treat fibrotic complications in patients.
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Other epigenetic regulators, including MECP2, EZH1/2, BRD4, SIRT1, KDM4D, and TET3, can contribute to chemically induced liver fibrosis.
“Other epigenetic regulators, such as methyl CpG binding protein 2 (MECP2), enhancer of zeste homolog 1/2 (EZH1/2), bromodomain-containing protein 4 (BRD4), Sirtuin 1 (SIRT1), lysine-specific demethylase 4D (KDM4D), and tet methylcytosine dioxygenase 3 (TET3), can contribute to chemically-induced liver fibrosis (174-178) (179, 180) (181).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [174]
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References 25 · Cited by 211
- Authors
- Ding, N., Hah, N., Yu, R. T., Sherman, M. H., Benner, C., Leblanc, M., He, M., Liddle, C., Downes, M., & Evans, R. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Razzavi Newman Integrated Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA 92037;
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;
- The University of Sydney (AU)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-12-07
- Volume
- 112
- Issue
- 51
- Pages
- 15713-15718
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4697417
- OpenAlex
- W2196306129
- Cited by
- 211
- References
- 25
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 11 · 2023: 32 · 2022: 21 · 2021: 20 · 2020: 18 · 2019: 28 · 2018: 22 · 2017: 23 · 2016: 9 · 2015: 2
- FWCI
- 11.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (K01DK102867, DK057978, DK090962, HL105278, HL088093, ES010337, CA014195)
- Department of Health, Australian Government | National Health and Medical Research Council (512354, 632886)
- Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002)
- Samuel Waxman Cancer Research Foundation (n/a)
- Howard Hughes Medical Institute (Ronald M. Evans)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- BRD4, liver fibrosis, hepatic stellate cells, myofibroblast activation, JQ1, BET proteins, bromodomain inhibitors, enhancer binding, transcriptional regulation, carbon tetrachloride-induced fibrosis, liver cirrhosis, therapeutic target
- MeSH terms
- Bromodomain Containing Proteins, Animals, Azepines, Cells, Cultured, Liver Cirrhosis, Experimental, Male, Mice, Inbred C57BL, Nuclear Proteins, Transcription Factors, Triazoles, Mice, Hepatic Stellate Cells
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