MTHFR epigenetic derepression protects against diabetes cardiac fibrosis

Background: Diabetes cardiac fibrosis is associated with altered DNA methylation of fibrogenic genes; however, the underlying mechanisms remain unclear.Objectives: In this study, we investigate the critical role of DNA methylation aberration-associated suppression of MTHFR in diabetes cardiac fibrosis, and the protective effects of folate on diabetes cardiac fibrosis, using cultured cells, animal models, and clinical samples.Methods and results: Herein, we report that DNA methylation repression of MTHFR, critically involved in diabetes cardiac fibrosis, mediates the significant protective effects of folate in a mouse model of diabetes cardiac fibrosis induced by STZ. Heart MTHFR expression was markedly suppressed in diabetes cardiac fibrosis patients and mice, accompanied by increased DNMT3A and MTHFR promoter methylation. Knockdown of DNMT3A deme-thylated MTHFR promoter, recovered the MTHFR loss, and alleviated the diabetes cardiac fibrosis pathology and cardiac fibroblasts pyroptosis. Mechanistically, DNMT3A epigenetically repressed MTHFR expression via methylation of the promoter. Interestingly, folate supplementation can rescue the effect of MTHFR loss in dia-betes cardiac fibrosis, suggesting that inactivation of MTHFR through epigenetics is a critical mediator of dia-betes cardiac fibrosis.Conclusions: The current study identifies that MTHFR repression due to aberrant DNMT3A elevation and sub-sequent MTHFR promoter hypermethylation is likely an important epigenetic feature of diabetes cardiac fibrosis, and folate supplementation protects against diabetes cardiac fibrosis.