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.

DNA低甲基化在系统性红斑狼疮（SLE）的发病机理中起重要作用。在这里，我们调查了3-羟基丁酸脱氢酶2（BDH2），细胞内铁稳态的调节剂，是否参与调节狼疮CD4 ⁺ T细胞中的DNA低甲基化和高羟甲基化。我们的结果表明，与健康对照组相比，狼疮CD4 ⁺ T细胞中BDH2表达降低，细胞内铁升高，总体DNA羟甲基化水平升高，而甲基化水平降低。减少的BDH2通过增加CD4 ^+中的细胞内铁而导致DNA高羟甲基化和低甲基化T细胞，导致免疫相关基因的过度表达。此外，我们表明BDH2是miR-21的靶基因。miR-21通过抑制BDH2表达来促进CD4 ⁺ T细胞中的DNA脱甲基。我们的数据表明，由BDH2缺乏引起的CD4 ⁺ T细胞中铁稳态的失调有助于SLE中的DNA去甲基化和自我反应性T细胞。