Mthfd2, also known as methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, is a mitochondrial one-carbon folate metabolic enzyme. It is involved in the one-carbon metabolism pathway, which is crucial for processes like de novo purine synthesis, DNA and histone methylation, and maintaining redox balance [2,3,4,5]. It has been found to be highly expressed in embryos and many tumors, with low or no expression in most adult differentiated tissues [7].

Mthfd2 deficiency in mice models has shown diverse impacts. In T cells, it promotes de novo purine synthesis, proliferation, and inflammatory cytokine production, and also prevents inappropriate FoxP3 up-regulation in Th17 cells while promoting Treg cell differentiation [2]. In macrophages, Mthfd2 suppresses the polarization of interferon-γ-activated macrophages but enhances that of interleukin-4-activated macrophages by interacting with PTEN to enhance Akt activation [1]. In cancer, Mthfd2 promotes tumorigenesis. For example, in triple-negative breast cancer, its knockdown suppresses cell proliferation, apoptosis, migration, and invasion, and enhances ferroptosis [3]. In gastric cancer, Mthfd2 knockdown reduces cellular NADPH/NADP + ratio, mitochondrial function, and increases ROS levels, leading to cell death under hypoxia [4]. In glioblastoma, RNAi-mediated Mthfd2 depletion hampers cell proliferation and induces apoptosis, and is linked to the unfolded protein response [5]. In acute myeloid leukemia, Mthfd2 inhibitors reduce replication fork speed, induce replication stress, and lead to apoptosis [6].

In conclusion, Mthfd2 is a key enzyme in one-carbon metabolism with significant non-metabolic functions. Studies using gene knockout or knockdown models have revealed its role in immune cell function, especially in T cells and macrophages, and its contribution to cancer development, including tumor cell growth, metastasis, and immune evasion. These findings suggest Mthfd2 could be a potential therapeutic target for treating inflammatory diseases and cancers.