Epigenetic and non-coding RNA modulation by flavonoids in cancer: mechanistic insights and therapeutic potential

Plant-derived polyphenolic compounds, such as flavonoids, have attracted interest due to their potential to modulate epigenetic processes linked to the onset of disease. Epigenetic regulation alters gene expression without changing the DNA sequence. The main mechanisms that mediate it include DNA methylation, non-coding RNAs, and histone modification. As cancer develops and spreads, changes in these epigenetic pathways are often observed. This narrative review examines preclinical and clinical evidence on the modulation of these pathways by flavonoids in cancer. Mainly in cell-line and animal models, flavonoids such as quercetin, apigenin, luteolin, and genistein have been reported to modulate histone acetyltransferases, histone deacetylases, DNA methyltransferases, selected non-coding RNAs, and chromatin-remodeling pathways, with downstream effects on gene expression programs related to tumor growth. Curcumin, a non-flavonoid polyphenol, is discussed separately where clinical data are considered. Despite these findings, several challenges persist, particularly limited bioavailability and inconsistencies between experimental and clinical results. Clinical trials of curcumin have reported antitumor outcomes but did not measure epigenetic endpoints, so the mechanistic findings have not yet been validated in patients. Clinical studies that include epigenetic biomarker endpoints are needed before any therapeutic role can be established.