NT5M (5',3'-nucleotidase, mitochondrial) is a mitochondrial enzyme that dephosphorylates 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides, protecting mitochondrial DNA replication from excess dTTP accumulation 1. The enzyme preferentially processes deoxynucleoside-5'-phosphates and is encoded by a nuclear gene located on chromosome 17.2, within a region associated with Smith-Magenis syndrome 1. NT5M has marginal activity toward dIMP and dGMP, suggesting substrate specificity in nucleotide catabolism. Beyond nucleotide metabolism, emerging evidence implicates NT5M in immune regulation and disease pathogenesis. Decreased NT5M expression correlates with poor clinical outcomes in pancreatic adenocarcinoma, where downregulation associates with increased CXCL8 expression and PD-L1 upregulation, promoting immune evasion 2. Conversely, NT5M is identified as a genetic risk factor for intracranial aneurysms (OR: 1.91) and aneurysmal subarachnoid hemorrhage (OR: 2.13) in genome-wide association studies 3. NT5M expression is also suppressed by tenofovir treatment in HIV-target cells, with implications for inflammatory responses 4. While NT5M mutations are not commonly detected in mitochondrial DNA depletion syndrome, the gene remains relevant for genetic counseling 5. NT5M may serve as a potential viral protease substrate in Zika virus infection 6.