Beyond the Well-Known Phytochemicals: Cryptic Plant-Derived Histone Acetyltransferase (HAT) and Histone Deacetylase (HDAC) Modulators as Epigenetic Adjuvants in Cancer Therapy

Epigenetic dysregulation constitutes a fundamental molecular hallmark of oncogenesis, arising from aberrant alterations in chromatin architecture and transcriptional regulation that disrupt cellular differentiation, sustain malignant phenotypes, promote therapeutic resistance, and facilitate tumor initiation and progression. Among the principal epigenetic mechanisms, histone acetylation is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), making these enzymes attractive targets for pharmacological intervention. Although several synthetic epigenetic drugs have entered clinical practice, their therapeutic utility may be constrained by limited selectivity, toxicity, and adaptive resistance, prompting the continued investigation of structurally diverse natural compounds. The review examines comparatively underexplored plant-derived phytochemicals with reported or proposed HAT- and/or HDAC-modulatory properties, focusing on parthenolide, anacardic acid, formononetin, plumbagin, and allicin and its derivatives, including S-allylmercaptocysteine (SAMC). The available evidence indicates that these compounds can influence epigenetic processes through distinct, pleiotropic, mechanisms, potentially affecting cellular proliferation, apoptosis, differentiation, and responses to anticancer treatment. Collectively, these findings support the further investigation of cryptic plant-derived HAT/HDAC modulators as candidate epigenetic adjuvants, while underscoring the need for rigorous mechanistic validation, pharmacokinetic characterization, and translational assessment.