ENTPD3 (ectonucleoside triphosphate diphosphohydrolase 3) is a plasma membrane-associated enzyme that catalyzes the sequential hydrolysis of nucleoside triphosphates (NTPs) and diphosphates (NDPs) to nucleoside monophosphates, with preference for ATP 1234. This enzymatic activity regulates extracellular nucleotide levels and purinergic signaling pathways 1234. ENTPD3 demonstrates protective roles in multiple disease contexts: in hepatocytes, it protects against ischemia-reperfusion injury by controlling ATP concentrations and P2 receptor signaling 5. In pancreatic beta cells, ENTPD3 expression is enhanced by certain DYRK1A inhibitors alongside other differentiation markers 6. The enzyme serves as a biomarker in various pathological conditions, showing downregulation in type 2 diabetes mellitus where it correlates with immune cell infiltration patterns 7. In osteoarthritis, extracellular vesicle-derived ENTPD3 alleviates mitochondrial dysfunction in chondrocytes through ENPP1-mediated suppression of AKT/Notch2 pathways 8. Additionally, ENTPD3 expression is reduced in Parkinson's disease substantia nigra, likely reflecting neuronal loss 9. These findings highlight ENTPD3's critical role in cellular energy homeostasis and its therapeutic potential across multiple disease contexts.