ENTPD6 (ectonucleoside triphosphate diphosphohydrolase 6) is a nucleotide-hydrolyzing enzyme that catalyzes the breakdown of nucleoside triphosphates and diphosphates in a calcium- or magnesium-dependent manner, with strong preference for nucleoside diphosphates including GDP, IDP, and UDP 123. The membrane-bound form localizes to the Golgi apparatus where it may support glycosylation reactions, while its released extracellular form catalyzes hydrolysis of extracellular nucleotides 123. ENTPD6's biological relevance extends to multiple disease contexts: genome-wide association studies identified rare coding variants in ENTPD6 associated with increased body mass index 4, and elevated ENTPD6 protein levels were identified as a genetic risk factor for visceral obesity with potential therapeutic targeting 5. In reproductive biology, ENTPD6 emerged as a candidate non-obstructive azoospermia pathogenic gene through yeast functional screening, where its guanosine diphosphatase activity proved essential for meiosis and pre-meiotic S phase entry 6. ENTPD6 was also identified as a hub gene in COVID-19-associated male infertility with diagnostic potential 7. Additionally, ENTPD6 expression modulates cisplatin sensitivity in testicular cancer through E-cadherin interactions and represents a potential chemoresistance biomarker 8. The nucleoside-diphosphatase functional gene set containing ENTPD6 shows significant association with pyrimidine antimetabolite responses 9.