DNA hypomethylation plays an important role in the pathogenesis of systemic 
lupus erythematosus (SLE). Here we investigated whether 3-hydroxy butyrate 
dehydrogenase 2 (BDH2), a modulator of intracellular iron homeostasis, was 
involved in regulating DNA hypomethylation and hyper-hydroxymethylation in lupus 
CD4+ T cells. Our results showed that BDH2 expression was decreased, 
intracellular iron was increased, global DNA hydroxymethylation level was 
elevated, while methylation level was reduced in lupus CD4+ T cells compared 
with healthy controls. The decreased BDH2 contributed to DNA 
hyper-hydroxymethylation and hypomethylation via increasing intracellular iron 
in CD4+ T cells, which led to overexpression of immune related genes. Moreover, 
we showed that BDH2 was the target gene of miR-21. miR-21 promoted DNA 
demethylation in CD4+ T cells through inhibiting BDH2 expression. Our data 
demonstrated that the dysregulation of iron homeostasis in CD4+ T cells induced 
by BDH2 deficiency contributes to DNA demethylation and self-reactive T cells in 
SLE.