HS3ST2 (heparan sulfate-glucosamine 3-sulfotransferase 2) is a Golgi and plasma membrane-localized sulfotransferase that catalyzes 3-O-sulfation of glucosamine residues on heparan sulfate (HS) chains 1. Unlike HS3ST1, HS3ST2 does not convert non-anticoagulant to anticoagulant heparan sulfate 1. Structurally, HS3ST2 uniquely localizes to the plasma membrane via its catalytic domain and syndecan-2 interaction, distinguishing it from the Golgi-resident HS3ST3B isoform 2. HS3ST2 dysregulation associates with multiple pathologies. In endometrial cancer, HS3ST2 hypermethylation increases from healthy (8.52±2.57) to hyperplastic (33.76±20.66) to cancerous tissues (34.49±18.39), serving as a methylation biomarker 3. In breast cancer, HS3ST2 reexpression enhances invasiveness through MAP kinase and Tcf4-dependent upregulation of matrix metalloproteinases and cadherins 4. HS3ST2 expression also induces tau aggregation in Alzheimer's disease models through intracellular 3-O-sulfated HS accumulation 5. In endometriosis, miR-100-mediated HS3ST2 downregulation promotes endometrial stromal cell proliferation and epithelial-mesenchymal transition 6. Additionally, HS3ST2+ macrophages associate with atherosclerosis and cerebrovascular events in carotid plaques 7, while HS3ST2 methylation status predicts cervical adenocarcinoma development 8.