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MTHFD2: A Retrospective and a Glance into the Future

Costas Koufaris¹, Vicky Nicolaidou²

¹Cyprus Cancer Research Institute, Nicosia 2109, Cyprus.

International Journal of Molecular Sciences

|November 27, 2025

Abstract:

The 1985 confirmation by Mejia and MacKenzie of mammalian NAD-dependent methylenetetrahydrofolate dehydrogenase activity launched four decades of research on methylenetetrahydrofolate dehydrogenase (NAD⁺-dependent), methenyltetrahydrofolate cyclohydrolase 2 (MTHFD2). This review provides a retrospective on four decades of advancements on MTHFD2 that have revealed its key roles in the folate pathway, amino acid and redox homeostasis, and the metabolism of cancer and immune cells. We trace the initial biochemical characterization of the enzyme, highlight pivotal discoveries regarding MTHFD2's metabolic and non-canonical roles, and discuss the current state of knowledge and future prospects.

Keywords:

MTHFD2 one-carbon metabolism retrospective

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