Natural histone deacetylase inhibitions from legumes: Exploring epigenetics modulation through systems biology

Epigenetic regulation, particularly histone deacetylases (HDACs), is critical for gene expression, chromatin remodeling, and cellular function. While synthetic HDAC inhibitors (HDACi) have shown promise in cancer treatment, their clinical utility is frequently constrained by toxicity, poor isoform specificity, and inferior performance in solid tumors. In recent years, there has been a rising focus on natural chemicals, particularly (poly)phenols produced from legumes, as safer and more selective alternatives. This review comprehensively examines the existing literature on legume-derived (poly)phenols, including genistein, daidzein, quercetin, and kaempferol, and their role as natural HDACis. It discusses their chemical diversity, HDAC inhibitory mechanisms, epigenetic influence, and associated biological activities such as anti-inflammatory, anticancer, and neuroprotective properties. In vitro and in vivo research on HDAC regulation by legume (poly)phenols are rigorously explored, as well as comparative insights into synthesized HDACi. This article also covers bioavailability issues, metabolism, and formulation options for improving therapeutic efficacy; highlights the therapeutic potential of legume (poly)phenols as epigenetic modulators by combining findings from molecular, pharmacological, and nutritional investigations: and calls for additional research into their use in nutraceutical development and disease treatment.