BRD4 as an emerging epigenetic therapeutic target for inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder, mainly comprising two subtypes: ulcerative colitis (UC) and Crohn's disease (CD). IBD, featured by recurrent symptoms and significant morbidity, poses a significant threat to global health and has an adverse impact on quality of life. Currently, there is no curative therapy for IBD, and the available medications are only for managing the disease condition, likely owing to the insufficient understanding of the underlying pathophysiology processes involved in IBD, and the lack of safe and effective medicines. Thus, novel targeted therapies for IBD are urgently needed for better efficacy with an improved adverse event profile. As the most extensively studied member of bromodomain and extra terminal domain (BET) family proteins, bromodomain-containing protein 4 (BRD4) is emerging as a promising epigenetic therapeutic target for IBD. Pharmacological inhibition of BRD4 with selective small molecule inhibitors shows potent anti-inflammatory effects in both in vitro and different IBD mouse models. Herein, we summarize current knowledge in understanding the role of BRD4 in the pathogenesis and development of IBD, and the clinical landscape of developing BET/BRD4 inhibitors and emerging BRD4-targeted degraders as promising therapeutical alternatives. Challenges and opportunities, as well as future directions in drug discovery by targeting BRD4 are also briefly discussed.