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Published on: February 10, 2015
BRD4: an effective target for organ fibrosis
Qun Wei1, Cailing Gan1, Meng Sun1
1Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Abstract:
Fibrosis is an excessive wound-healing response induced by repeated or chronic external stimuli to tissues, significantly impacting quality of life and primarily contributing to organ failure. Organ fibrosis is reported to cause 45% of all-cause mortality worldwide. Despite extensive efforts to develop new antifibrotic drugs, drug discovery has not kept pace with the clinical demand. Currently, only pirfenidone and nintedanib are approved by the FDA to treat pulmonary fibrotic illness, whereas there are currently no available antifibrotic drugs for hepatic, cardiac or renal fibrosis. The development of fibrosis is closely related to epigenetic alterations. The field of epigenetics primarily studies biological processes, including chromatin modifications, epigenetic readers, DNA transcription and RNA translation. The bromodomain and extra-terminal structural domain (BET) family, a class of epigenetic readers, specifically recognizes acetylated histone lysine residues and promotes the formation of transcriptional complexes. Bromodomain-containing protein 4 (BRD4) is one of the most well-researched proteins in the BET family. BRD4 is implicated in the expression of genes related to inflammation and pro-fibrosis during fibrosis. Inhibition of BRD4 has shown promising anti-fibrotic effects in preclinical studies; however, no BRD4 inhibitor has been approved for clinical use. This review introduces the structure and function of BET proteins, the research progress on BRD4 in organ fibrosis, and the inhibitors of BRD4 utilized in fibrosis. We emphasize the feasibility of targeting BRD4 as an anti-fibrotic strategy and discuss the therapeutic potential and challenges associated with BRD4 inhibitors in treating fibrotic diseases.
Insights
Targeting bromodomain-containing protein 4 (BRD4), a key epigenetic regulator, shows promise for treating organ fibrosis. BRD4 inhibition presents a potential antifibrotic strategy, though clinical application faces challenges.
Area of Science:
- Epigenetics
- Molecular Biology
- Drug Discovery
Background:
- Fibrosis, a major cause of organ failure and mortality, lacks effective treatments beyond pulmonary indications.
- Epigenetic alterations, particularly involving bromodomain and extra-terminal domain (BET) proteins, are critical in fibrosis development.
- Bromodomain-containing protein 4 (BRD4) is a key BET protein involved in pro-fibrotic gene expression.
Purpose of the Study:
- To review the role of BET proteins and BRD4 in organ fibrosis.
- To discuss the progress of BRD4 inhibitors in preclinical and clinical fibrosis research.
- To evaluate the therapeutic potential and challenges of targeting BRD4 for antifibrotic strategies.
Main Methods:
- Literature review of studies on BET proteins, BRD4, and fibrosis.
- Analysis of preclinical data on BRD4 inhibition in fibrotic models.
- Examination of current BRD4 inhibitors and their clinical development status.
Main Results:
- BRD4 regulates genes associated with inflammation and fibrosis.
- Inhibition of BRD4 has demonstrated significant antifibrotic effects in preclinical studies.
- Several BRD4 inhibitors are under investigation, but none are yet approved for clinical use in fibrosis.
Conclusions:
- Targeting BRD4 is a feasible and promising antifibrotic strategy.
- Further research and clinical trials are needed to overcome challenges and realize the therapeutic potential of BRD4 inhibitors for fibrotic diseases.
