Polyphenolic compounds remodeling acetylation modifications: Unveiling potential therapeutic strategies for hematologic malignancies

Aberrant lysine acetylation modifications driven epigenetic dysregulation of gene expression represents a central mechanism underlying high relapse rates and drug resistance in hematologic malignancies. Developing novel therapeutic strategies that target chromatin homeostasis and gene regulatory networks is thus critical to overcoming current clinical challenges. Polyphenolic compounds are a class of natural phytochemicals characterized by phenolic hydroxyl groups that include candidate lysine acetylation modulators showing promise for intervention in hematologic malignancies because of their multi-target synergistic mechanisms and favorable toxicity profiles. These compounds dynamically modulate the activities of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), orchestrating epigenetic reprogramming that significantly reduces the incidence of drug resistance with low risk of off-target toxicity. This review comprehensively synthesizes our current understanding of polyphenol-mediated acetylation regulation and delineates their unique therapeutic advantages in hematologic malignancy treatment. By systematically mining multidimensional mechanistic data from the literature describing polyphenol-driven acetylation remodeling, we have established structure-activity relationships (SARs) correlating polyphenolic scaffolds with acetylation modulation, with the goal of elucidating specific structural advantages in epigenetic targeting from a medicinal chemistry perspective. We also investigated an innovative targeted delivery paradigm leveraging integrated nanotechnology platforms, which may advance precision delivery of polyphenolic compounds and provide novel strategies and new directions for anti-hematologic malignancy drug development.