NT5C3A (5'-nucleotidase, cytosolic IIIA) is a pyrimidine-metabolizing enzyme that catalyzes the dephosphorylation of cytidine monophosphate (CMP) and other nucleoside monophosphates 1. Beyond nucleotide catabolism, NT5C3A functions as a negative regulator of inflammatory signaling. Type I interferon induces NT5C3A expression through IRF1-dependent mechanisms, and the enzyme suppresses NF-κB-mediated cytokine production by increasing NAD+ levels and activating the NAD+-dependent deacetylases SIRT1 and SIRT6, which deacetylate histone H3 and the NF-κB subunit RelA 2. This pathway represents an anti-inflammatory feedback mechanism during immune responses 3. NT5C3A is also part of the antiviral response, with expression upregulated during influenza A virus infection 4. Clinically, NT5C3A deficiency causes pyrimidine 5'-nucleotidase (P5N) deficiency, a rare erythrocyte enzymopathy presenting as nonspherocytic hemolytic anemia 56. Loss-of-function mutations in NT5C3A result in accumulation of pyrimidine nucleotides and hemolysis. Additionally, NT5C3A has emerged as a candidate biomarker for disease activity monitoring in chr7 inflammatory demyelinating polyneuropathy 7, and altered NT5C3A methylation is associated with maternal atopy in neonatal cord blood 8.