NT5C (5',3'-nucleotidase, cytosolic) is a cytosolic enzyme that dephosphorylates deoxyribonucleoside monophosphates, showing preference for dUMP and dTMP substrates 1. The enzyme catalyzes the conversion of nucleoside monophosphates to nucleosides and inorganic phosphates, playing a critical role in nucleotide pool homeostasis and pyrimidine metabolism 2. NT5C localizes to the cytosol and nucleus, with potential mitochondrial association 1. Regarding disease relevance, NT5C has emerged as a significant pharmacogenomic target. Loss-of-function studies demonstrated that NT5C knockdown impacts sensitivity to 5-fluorouracil (5-FU), a chemotherapy agent used for colorectal cancer 3. Genetic analyses identified NT5C as a protein with strong genetic support for involvement in non-alcoholic fatty liver disease (NAFLD) 4. Additionally, NT5C expression changes were observed in glaucoma-related trabecular meshwork dysfunction 5 and in neurodevelopmental outcomes associated with prenatal air pollution exposure 6. Clinically, NT5C's metabolic functions have therapeutic implications. Suppression of NT5C enzymes increases AMP availability, enhancing AMPK phosphorylation and improving metabolic flexibility in skeletal muscle, potentially benefiting type 2 diabetes management 2. The enzyme also metabolizes nucleoside analog drugs including fludarabine 7, suggesting its importance in drug disposition and efficacy.