The role of bromodomain protein-4 (BRD4) in the regulation of stem cell differentiation and proliferation: molecular mechanisms and therapeutic perspectives

The aim was to identify clinical and biological situations in which BRD4 inhibition provides anti-tumor and/or anti-fibrotic benefit, and when it may interfere with physiological tissue regeneration. A targeted search of PubMed, Scopus, and Web of Science identified original research and clinical trials. We included studies on BRD4 function at super-enhancers (genomic regions that strongly amplify gene transcription), data on regeneration and fibrosis, and reports on BET inhibitors and BRD4 degraders. BRD4 is a key node sustaining the activity of genes that determine cellular “behavior”; consequently, tumors dependent on superenhancers are vulnerable to BRD4-directed interventions. The most convincing clinical effect has been shown in myelofibrosis: adding a BET inhibitor to ruxolitinib outperforms standard monotherapy on major endpoints. In prostate cancer, combinations with BET inhibitors show a reproducible signal of efficacy in selected subgroups, whereas BET monotherapy in solid tumors is often only modestly active. At the same time, prolonged or “total” BRD4 blockade can impair functions of tissues that require BRD4 for homeostasis (e.g., the heart and actively forming bone), while BET inhibition reduces myofibroblast activity and dermal fibrosis in preclinical models. Modality matters: panBET/BD1-oriented regimens are more appropriate in oncology; BD2-selective strategies fit inflammatory/fibrotic contexts; PROTAC-based approaches are promising but require targeted delivery and careful safety monitoring. BRD4 inhibition is justified where pathological super-enhancer–dependent transcription predominates and is more effective as part of well-designed combination regimens with biomarker-guided patient selection. Prolonged systemic exposure should be avoided during active tissue repair, favoring short, local, and/or domainselective regimens.

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