Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes expression of a large number of antioxidant genes and multiple studies have described oxidative stress and impaired methylation in autism spectrum disorder (ASD), including decreased brain levels of methylcobalamin(III) (MeCbl). Here we report decreased expression of the Nrf2 gene (NFE2L2) in frontal cortex of ASD subjects, as well as differences in other genes involved in redox homeostasis. In pooled control and ASD correlation analyses, hydroxocobalamin(III) (OHCbl) was inversely correlated with NFE2L2 expression, while MeCbl and total cobalamin abundance were positively correlated with NFE2L2 expression. Levels of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and cystathionine were positively correlated with NFE2L2 expression, while homocysteine (HCY) was negatively correlated. The relationship between Nrf2 activity and cobalamin was further supported by a bioinformatics-based comparison of cobalamin levels in different tissues with expression of a panel of 40 Nrf2-regulated genes, which yielded a strong correlation. Lastly, Nrf2-regulated gene expression was also correlated with expression of intracellular cobalamin trafficking and processing genes, such as MMADHC and MTRR. These findings highlight a previously unrecognized relationship between the antioxidant-promoting role of Nrf2 and cobalamin status, which is dysfunctional in ASD.

核因子红细胞 2 相关因子 2 (Nrf2) 促进大量抗氧化基因的表达，多项研究描述了自闭症谱系障碍 (ASD) 中的氧化应激和甲基化受损，包括脑内甲基钴胺素 (III) (MeCbl) 水平降低. 在这里，我们报告了 ASD 受试者额叶皮层中 Nrf2 基因 (NFE2L2) 的表达降低，以及参与氧化还原稳态的其他基因的差异。在汇总对照和 ASD 相关性分析中，羟钴胺素 (III) (OHCbl) 与 NFE2L2 表达呈负相关，而 MeCbl 和总钴胺素丰度与 NFE2L2 表达呈正相关。蛋氨酸、S-腺苷甲硫氨酸(SAM)、S的水平-腺苷同型半胱氨酸（SAH）和胱硫醚与NFE2L2表达呈正相关，而同型半胱氨酸（HCY）呈负相关。Nrf2 活性和钴胺素之间的关系得到了基于生物信息学的不同组织中钴胺素水平与一组 40 个 Nrf2 调节基因表达的比较的进一步支持，这产生了很强的相关性。最后，Nrf2 调节的基因表达也与细胞内钴胺素运输和加工基因（如 MMADHC 和 MTRR）的表达相关。这些发现强调了 Nrf2 的抗氧化促进作用与钴胺素状态之间以前未被认识的关系，钴胺素状态在 ASD 中是功能失调的。