Metabolic regulation of DNA methylation across the cardiovascular–kidney–metabolic continuum: mechanisms, tissue specificity, and clinical translation

Cardiovascular–kidney–metabolic (CKM) syndrome describes an interconnected continuum of metabolic, cardiovascular, and kidney dysfunction driven by persistent metabolic stress. Although DNA methylation has been extensively studied in individual metabolic disorders, how systemic metabolic perturbations converge on the methylation machinery and generate tissue-specific responses across this continuum remains unclear. This review integrates biochemical studies, human epigenome-wide association studies, target-tissue methylomes, causal-inference analyses, and intervention studies. We examine three interconnected routes by which metabolism may shape DNA methylation: altered methyl-donor availability, impaired TET-dependent demethylation, and stress-dependent changes in chromatin and cell state. One-carbon metabolism, tricarboxylic acid-cycle intermediates, and redox imbalance can influence DNA methyltransferase and ten-eleven translocation enzyme activity, linking metabolic state to locus- and tissue-specific methylation dynamics. Evidence is synthesized across adipose tissue, liver, skeletal muscle, pancreatic islets, kidney, and cardiovascular tissues. We distinguish peripheral biomarkers from target-organ mechanisms and evaluate cell-composition confounding, the inability of conventional bisulfite assays to resolve 5-methylcytosine from 5-hydroxymethylcytosine, and reverse causation. Methylation quantitative trait loci, Mendelian randomization, colocalization, multi-omic integration, and longitudinal intervention studies are considered as complementary approaches for prioritizing clinically relevant loci. DNA methylation may provide a context-dependent interface between metabolic stress and persistent organ dysfunction in CKM syndrome. Longitudinal, cell-resolved, multi-tissue studies that integrate methylomics with metabolomics and functional perturbation are needed to distinguish exposure markers from mediators and therapeutic targets.