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

  • Authors:
    • Pablo Michael Navarro‑Rodríguez
    • Ramón Francisco Bajeca‑Serrano
    • Francisco Javier Turrubiates‑Hernández
    • Hazael Ramiro Ceja‑Gálvez
    • Jorge Hernández‑Bello
    • Cristian Oswaldo Hernández‑Ramírez
    • Saúl Ramírez‑de Los Santos
    • José Francisco Muñoz‑Valle
  • View Affiliations / Copyright

    Affiliations: Department of Molecular Biology and Genomics, University Center of Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico, Department of Clinical Medicine, Institute of Research in Biomedical Sciences, University Center of Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
    Copyright: © Navarro‑Rodríguez et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 70
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    Published online on: January 22, 2026
       https://doi.org/10.3892/ijmm.2026.5741
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Abstract

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.17

View Figures

Figure 1

(A) Dietary sources of folate and
general structure. Dietary folates, comprising three main
components (pterin, p-aminobenzoic acid and a glutamate
chain), are ingested as polyglutamates and hydrolyzed to
monoglutamates by the enzyme GCPII in the intestinal brush border.
(B) Intestinal absorption of folate. Folate uptake occurs through
transporters located in enterocytes, primarily the PCFT and the
RFC, as well as through FRα/FRβ present in other cell types. (C) In
folate metabolism, within intestinal cells, folate is sequentially
reduced by DHFR to DHF and ultimately to its active form, THF. THF
is transported to 5,10-methylenetetrahydrofolate (5,10-MTHF) by
serine hydroxymethyltransferase (SHMT) and subsequently reduced by
the FAD-dependent enzyme MTHFR to 5-methylenetetrahydrofolate
(5-MTHF). The latter donates its methyl group to homocysteine to
regenerate methionine, in a reaction catalyzed by MTR that requires
vitamin B12. Methionine is then converted by MAT into
SAM, the universal methyl donor, in an ATP-dependent process. This
sequence associates folate metabolism with methylation reactions
that are key for nucleotide synthesis and epigenetic regulation.
GCPII, glutamate carboxypeptidase II; PCFT, proton-coupled folate
transporter; RFC, reduced folate carrier; FR, folate receptor;
DHFR, dihydrofolate reductase; THF, tetrahydrofolate; 5,10-MTFH,
5,10-methylenetetrahydrofolate; SHMT, serine
hydroxymethyltransferase; MTR, methionine synthase; MAT, methionine
adenosyltransferase; SAM, S-adenosylmethionine.

Figure 2

Schematic representation of the
folate and methionine cycles illustrating their interconnection
with one-carbon metabolism, methylation reactions and
transsulfuration. Dietary folate is initially reduced to DHF and
THF by DHFR. THF is converted to 5,10-MTHF by SHMT (a vitamin
B6-dependent enzyme) and subsequently reduced to 5-MTHF
by MTHFR. 5-MTHF donates a methyl group to Hcy via MTR (a vitamin
B12-dependent enzyme), thereby regenerating methionine.
Methionine is then converted to SAM by MAT. SAM serves as the
universal methyl donor for DNA, RNA, protein and lipid methylation.
Following methyl donation, SAM is converted to SAH, which is
hydrolyzed by AHCY to Hcy. Homocysteine can be remethylated by BHMT
using betaine as a methyl donor or diverted into the
transsulfuration pathway via CBS to generate cystathionine,
cysteine and ultimately glutathione. This pathway highlights the
biochemical integration of folate status, methylation potential and
redox homeostasis (97-99). DHR, dihydrofolate; THF,
tetrahydrofolate; DHFR, dihydrofolate reductase; 5,10-MTHF;
5,10-methylene-THF, SHMT, serine hydroxymethyltransferase; 5-MTHF,
5-methyl-THF; 5-MTHF, 5-methyl-THF; MTHFR,
methylenetetrahydrofolate reductase; Hcy, homocysteine; MTR,
methionine synthase; SAM, S-adenosylmethionine; MAT, methionine
adenosyltransferase; SAH; S-adenosylhomocysteine; AHCY,
adenosylhomocysteinase; BHMT, betaine-homocysteine
methyltransferase; CBS, cystathionine β-synthase; SAHH,
S-adenosylhomocysteine hydrolase.
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Copy and paste a formatted citation
Spandidos Publications style
Navarro‑Rodríguez PM, Bajeca‑Serrano RF, Turrubiates‑Hernández FJ, Ceja‑Gálvez HR, Hernández‑Bello J, Hernández‑Ramírez CO, Ramírez‑de Los Santos S and Muñoz‑Valle JF: <p><em>MTHFR</em>‑folate axis as a modulator of the epigenetic landscape in autoimmune diseases (Review)</p>. Int J Mol Med 57: 70, 2026.
APA
Navarro‑Rodríguez, P.M., Bajeca‑Serrano, R.F., Turrubiates‑Hernández, F.J., Ceja‑Gálvez, H.R., Hernández‑Bello, J., Hernández‑Ramírez, C.O. ... Muñoz‑Valle, J.F. (2026). <p><em>MTHFR</em>‑folate axis as a modulator of the epigenetic landscape in autoimmune diseases (Review)</p>. International Journal of Molecular Medicine, 57, 70. https://doi.org/10.3892/ijmm.2026.5741
MLA
Navarro‑Rodríguez, P. M., Bajeca‑Serrano, R. F., Turrubiates‑Hernández, F. J., Ceja‑Gálvez, H. R., Hernández‑Bello, J., Hernández‑Ramírez, C. O., Ramírez‑de Los Santos, S., Muñoz‑Valle, J. F."<p><em>MTHFR</em>‑folate axis as a modulator of the epigenetic landscape in autoimmune diseases (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 70.
Chicago
Navarro‑Rodríguez, P. M., Bajeca‑Serrano, R. F., Turrubiates‑Hernández, F. J., Ceja‑Gálvez, H. R., Hernández‑Bello, J., Hernández‑Ramírez, C. O., Ramírez‑de Los Santos, S., Muñoz‑Valle, J. F."<p><em>MTHFR</em>‑folate axis as a modulator of the epigenetic landscape in autoimmune diseases (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 70. https://doi.org/10.3892/ijmm.2026.5741
Copy and paste a formatted citation
x
Spandidos Publications style
Navarro‑Rodríguez PM, Bajeca‑Serrano RF, Turrubiates‑Hernández FJ, Ceja‑Gálvez HR, Hernández‑Bello J, Hernández‑Ramírez CO, Ramírez‑de Los Santos S and Muñoz‑Valle JF: <p><em>MTHFR</em>‑folate axis as a modulator of the epigenetic landscape in autoimmune diseases (Review)</p>. Int J Mol Med 57: 70, 2026.
APA
Navarro‑Rodríguez, P.M., Bajeca‑Serrano, R.F., Turrubiates‑Hernández, F.J., Ceja‑Gálvez, H.R., Hernández‑Bello, J., Hernández‑Ramírez, C.O. ... Muñoz‑Valle, J.F. (2026). <p><em>MTHFR</em>‑folate axis as a modulator of the epigenetic landscape in autoimmune diseases (Review)</p>. International Journal of Molecular Medicine, 57, 70. https://doi.org/10.3892/ijmm.2026.5741
MLA
Navarro‑Rodríguez, P. M., Bajeca‑Serrano, R. F., Turrubiates‑Hernández, F. J., Ceja‑Gálvez, H. R., Hernández‑Bello, J., Hernández‑Ramírez, C. O., Ramírez‑de Los Santos, S., Muñoz‑Valle, J. F."<p><em>MTHFR</em>‑folate axis as a modulator of the epigenetic landscape in autoimmune diseases (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 70.
Chicago
Navarro‑Rodríguez, P. M., Bajeca‑Serrano, R. F., Turrubiates‑Hernández, F. J., Ceja‑Gálvez, H. R., Hernández‑Bello, J., Hernández‑Ramírez, C. O., Ramírez‑de Los Santos, S., Muñoz‑Valle, J. F."<p><em>MTHFR</em>‑folate axis as a modulator of the epigenetic landscape in autoimmune diseases (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 70. https://doi.org/10.3892/ijmm.2026.5741
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