Targeting cancer epigenetic pathways with small-molecule modulators for potential therapeutic purposes

Epigenetic regulators exert critical functions in cancer initiation and progression by governing key processes-such as gene expression, chromatin remodeling, and cellular differentiation-without altering the underlying DNA sequence. Given the multitude of targetable nodes within epigenetic pathways and their central roles in tumorigenesis, disease progression, and drug resistance, the advancement of epigenetic therapies holds considerable promise for augmenting existing cancer treatment modalities. Recent pharmacological innovations have yielded diverse small-molecule inhibitors directed against principal epigenetic enzymes-namely DNA methyltransferases (DNMTs), histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone methyltransferases (HMTs). These agents have demonstrated potent therapeutic efficacy in both preclinical models and early-phase clinical trials by reprogramming the epigenetic landscape of malignant cells, potentiating conventional therapies, and overcoming resistance mechanisms. However, comprehensive assessments of their safety, selectivity, and resistance profiles remain incomplete, and systematic analyses of the clinical translation barriers for multitargeted epigenetic modulators are lacking. Accordingly, this review presents an in-depth analysis of the most recent advances in small-molecule epigenetic modulators, focusing on their mechanisms of action, therapeutic applications, and the challenges impeding their clinical development, with the aim of informing the rational design and optimization of next-generation epigenetic treatment strategies for cancer. FACTS.