MTHFR ‑folate axis as a modulator of the epigenetic landscape in autoimmune diseases (Review)

The one-carbon metabolism pathway, regulated by the methylenetetrahydrofolate reductase (MTHFR) enzyme, represents a key nexus where genetic predisposition and nutrient status converge to shape the epigenetic landscape of autoimmune diseases.The objective of the present review is to synthesize evidence of how the MTHFR-folate axis drives epigenomic patterns in these conditions.One of the main diseases involved is rheumatoid arthritis, where drug-naïve patients show T-cell and synovial hypomethylation with cytokine-driven dNMT suppression, a process aggravated by reduced folate availability and MTHFR polymorphisms that constrain S-adenosylmethionine supply.Similarly, in systemic lupus erythematosus, cd4 + T cells exhibit global hypomethylation with an interferon-skewed signature (such as IFI44L), associated with impaired MTHFR activity and a folate-dependent SAM:SAH imbalance that further diminishes dNMT function.Finally, in celiac disease, intestinal differential methylation, including LINE-1 hypomethylation, is observed, driven by gluten-induced villous atrophy and folate malabsorption.Overall, impaired one-carbon metabolism and MTHFR-dependent methylation capacity may be key determinants of epigenomic dysfunction underlying autoimmune disease and its clinical severity.