Abstract
DNA methyltransferases (DNMTs) regulate gene expression and genome stability by transferring a methyl group from S-adenosylmethionine to cytosine through a catalytic mechanism involving a conserved cysteine. Dysregulated DNA methylation contributes to cancer, chronic inflammation and persistent metabolic phenotypes, encouraging the development of non-nucleoside DNMT modulators. This narrative review examines whether electrophilic reactivity, particularly Michael acceptor chemistry, provides a plausible mechanistic framework for the reported DNMT-modulatory effects of structurally diverse natural compounds, evaluated across polyphenols, isothiocyanates, sesquiterpene lactones, alkaloids, terpenoids, polyketides and endogenous electrophilic lipids according to experimental level, distinguishing direct enzymatic inhibition from docking predictions, altered DNMT expression and broader cellular effects. The literature was retrieved from PubMed, Scopus and Web of Science and appraised with an explicit grading scheme that separates cell-free enzyme inhibition, proposed engagement of the catalytic cysteine, cellular changes in DNMT expression or methylation, and downstream biological effects. Curcumin and parthenolide provide notable precedents for catalytic-cysteine-directed hypotheses, whereas direct covalent engagement remains insufficiently demonstrated for most other candidates. The review also considers reversibility, electrophile selectivity, bioavailability and interactions with histone modifications, inflammatory signalling and the NAD+/sirtuin axis. Michael acceptor chemistry offers a useful hypothesis for prioritising natural DNMT modulators, but biochemical, structural and chemoproteomic validation is required before covalent DNMT inhibition can be regarded as a general mechanism or translated into therapeutic recommendations.