MTHFD2L is a bifunctional mitochondrial enzyme catalyzing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities in one-carbon (1C) metabolism 1. Unlike its paralog MTHFD2, MTHFD2L exhibits dual redox cofactor specificity, utilizing both NAD+ and NADP+ 2, and is constitutively expressed in normal adult tissues 3. Unlike the cancer-associated MTHFD2, MTHFD2L shows no association with proliferation or growth factor stimulation, making it unsuitable as a cancer drug target 3. However, MTHFD2L demonstrates emerging clinical significance in neurodegenerative disease. Genetic variations in MTHFD2L are linked to Alzheimer's disease (AD) risk, and enhancing mitochondrial 1C metabolism through MTHFD2L orthologs improves mitochondrial function and provides neuroprotection in AD models 4. Additionally, a circular RNA-encoded peptide from MTHFD2L (CM-248aa) suppresses gastric cancer progression through SET-PP2A pathway inhibition, though this represents a non-canonical function 5. MTHFD2L's role in maintaining mitochondrial redox homeostasis and cellular metabolism positions it as a potential therapeutic target for neurodegenerative diseases rather than cancer.