Beyond DNA Demethylation: Curcumin as a Context-Dependent Remodeler of the Epigenetic Landscape

Curcumin has attracted considerable attention for its pleiotropic effects on cellular signaling, inflammation, metabolism, and cancer biology. A growing body of evidence indicates that these effects coincide with alterations in the epigenetic landscape; however, a causal contribution of such alterations has seldom been established experimentally. Although curcumin has frequently been described as an epigenetic demethylating agent, accumulating evidence suggests more complex, context-dependent mechanisms, which involve DNA methylation, hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs. These changes may affect the accessibility and transcriptional activity of genes involved in cell identity, proliferation, differentiation, inflammation, and therapeutic response. The few genome-wide methylomic and transcriptomic studies available, mostly performed in a single cell line and at micromolar concentrations that exceed those reached in vivo, suggest that curcumin-induced epigenetic changes depend on cellular context, dose, and exposure conditions. This narrative review summarizes evidence published mainly from 2004 onward on the effects of curcumin on DNA methylation and hydroxymethylation, while integrating its interactions with histone modifications, chromatin organization, and non-coding RNA networks. We further discuss how these interconnected mechanisms contribute to the rewiring of gene regulatory programs and may underlie the biological and therapeutic effects of curcumin. Finally, we highlight the current limitations, including the poor bioavailability of curcumin, the non-specific chemistry of the molecule, and the scarcity of integrative multi-omics data, and we discuss what would be required to establish whether curcumin-induced epigenetic changes are relevant at pharmacologically attainable concentrations.