Wenju Zhang, Yumei Li, Ming-Ming Zhou, Lei Zeng
Bromodomain-containing protein 4 (BRD4) is a key transcriptional regulator in the bromodomain and extraterminal (BET) family. It promotes cancer and inflammation by binding to chromatin through its bromodomains. Although bromodomain inhibitors (e.g., BETi) show preclinical efficacy, their clinical application has been limited primarily by dose-limiting toxicities (DLTs), with resistance emerging as a secondary challenge. This motivates the development of strategies beyond conventional bromodomain inhibition. Here, we review emerging evidence that BRD4 sustains oncogenic programs through bromodomain-independent mechanisms, and discuss innovative approaches designed to overcome DLT. These include BRD4-targeted degraders, nonbromodomain ligands that disrupt scaffolding functions, post-translational modification (PTM) disruptors, and condensate modulators. We also discuss advances in chemically induced proximity (CIP) platforms that enable disease-state transcriptional reprogramming, and rational combination therapies (e.g., epigenetic-kinase inhibitors and BETi-immunotherapy integration) that minimize toxicity while addressing emerging resistance. Together, these approaches open new therapeutic frontiers for treating BRD4-driven diseases.