ENTPD5 is an endoplasmic reticulum (ER)-localized nucleotidase that hydrolyzes nucleoside diphosphates, particularly GDP, IDP, and UDP 1. Its primary function involves regulating protein N-glycosylation in the ER by hydrolyzing UDP, which acts as a feedback inhibitor of UDP-glucose:glycoprotein glucosyltransferases 1. This activity promotes protein reglucosylation, essential for proper glycoprotein folding and ER quality control 2. ENTPD5 maintains the calnexin/calreticulin cycle, affecting integrin expression and cellular adhesion properties 2. Beyond ER functions, ENTPD5 also hydrolyzes extracellular ATP to ADP, activating purinergic signaling pathways that regulate hepatic glucose and lipid metabolism 3. Clinically, ENTPD5 shows significant disease relevance as it is overexpressed in multiple cancers including ovarian, pancreatic, lung, and breast cancers 452. In epithelial ovarian cancer, ENTPD5 overexpression correlates with poor survival and promotes tumor growth and metastasis through the GRP78/p-eIF-2α/CHOP pathway 5. The enzyme also plays protective roles in diabetic kidney disease by alleviating ER stress-associated renal injury 1. These diverse functions establish ENTPD5 as both a metabolic regulator and potential therapeutic target in cancer treatment 6.