ENTPD8 is a canalicular ectonucleoside triphosphate diphosphohydrolase that catalyzes sequential hydrolysis of nucleoside triphosphates (NTPs) and diphosphates (NDPs) to nucleoside monophosphates (NMPs), contributing to regulation of extracellular nucleotide levels 1. The enzyme preferentially hydrolyzes ATP, UTP, ADP, and UDP, with substrate preference for triphosphonucleosides and adenine over uracil, but does not hydrolyze AMP 1. ENTPD8 functions predominantly in hepatocytes as the dominant source of hepatic NTPDase activity 2. In tissue-specific roles, ENTPD8 protects against liver ischemia-reperfusion injury by suppressing P2 receptor-mediated inflammatory responses through nucleotide hydrolysis 2, and similarly protects intestinal epithelial cells from DSS-induced inflammation by limiting P2Y6 receptor activation 3. Dysregulation of ENTPD8 is implicated in disease pathogenesis. In pancreatic cancer, ENTPD8 downregulation impairs the CTP dephosphorylation pathway, reducing cytidine formation in pyrimidine metabolism 4. ENTPD8 expression is altered in diabetic nephropathy 5 and affected by environmental exposure to BHPF in endometrial cells 6. DNA methylation at the ENTPD8 locus associates with working memory and cognitive abilities in aging 7, and ENTPD8 expression is reversibly altered by tobacco smoke exposure 8.