Advances of HDAC dual inhibitors in breast cancer treatment

Abstract

Breast cancer remains the most common prevalent malignancy among women globally, constituting the primary cause of cancer-associated mortality. While therapeutic advancements have been achieved, persistent challenges in treatment resistance, disease recurrence, and distant metastasis continue to undermine clinical outcomes. Histone deacetylases (HDACs), a conserved family of epigenetic regulators, catalyze the removal of acetyl groups from histone substrates, thereby orchestrating chromatin remodeling and transcriptional regulation. Beyond their canonical epigenetic functions, these enzymes critically modulate diverse oncogenic progresses, including cell proliferation, differentiation, and metastasis, positioning them as promising therapeutic targets in oncology. Recent studies have demonstrated the therapeutic prospects of dual-target inhibitors. Current evidence suggests such combinatorial approaches not only enhance anti-neoplastic efficacy through multi-modal mechanisms but also circumvent the drug resistance frequently observed in single-target therapy. This therapeutic paradigm shift underscores the clinical potential of HDAC-based dual inhibitors for breast cancer management. In this review, we systematically analyze recent advancements in dual-target HDAC inhibitors (HDACis), integrating mechanistic insights, preclinical evidences, and translational implications to establish a foundational framework for future therapeutic development and clinical implementation.