Unveiling the influence of polyphenols on histone modifications in human diseases

Histone N-terminal tails undergo diverse post-translational modifications, including methylation, acetylation, phosphorylation, ubiquitination, and ADP-ribosylation. Collectively, these modifications form a complex "histone code" that governs chromatin architecture and regulates DNA-related processes such as transcription, replication, and repair. Aberrant histone modification patterns are increasingly recognized as key contributors to the pathogenesis of cancer, neurodegenerative disorders, and cardiovascular diseases.

This review aims to provide a comprehensive overview of current evidence on the regulatory effects of dietary polyphenols on histone modifications and to evaluate their potential as natural epigenetic modulators for disease prevention and therapy.

Relevant literature from recent molecular, cellular, and animal studies was systematically analyzed to identify polyphenolic compounds that influence histone-modifying enzymes and associated signaling pathways. Fourteen representative polyphenols were included, comprising flavonoids (epigallocatechin gallate, anthocyanins, quercetin, luteolin, apigenin, genistein, and fisetin), stilbenes (resveratrol and pterostilbene), phenolic acids (gallic acid, caffeic acid, and ferulic acid), tannins (tannic acid), and curcumin.

Accumulating evidence demonstrates that these polyphenols act on one or more histone-modifying enzymes, particularly as histone deacetylase inhibitors, thereby modulating histone acetylation and methylation states. Such epigenetic modulation influences key gene expression pathways involved in inflammation, oxidative stress, apoptosis, and cell cycle regulation. Structural characteristics of polyphenols, including the number and position of hydroxyl groups and conjugation patterns, appear to determine their specificity and potency toward histone-modifying targets.

Dietary polyphenols represent promising, safe, and natural epigenetic agents capable of modulating histone modification dynamics. Elucidating the structure-activity relationships and molecular mechanisms underlying their interactions with histone-modifying enzymes will facilitate the development of polyphenol-based strategies for the prevention and treatment of human diseases.