HS3ST2 encodes a sulfotransferase that catalyzes 3-O-sulfation of glucosamine residues in heparan sulfate through transfer of a sulfo group from PAPS (3'-phospho-5'-adenylyl sulfate). Unlike the related enzyme HS3ST1, HS3ST2 does not convert non-anticoagulant heparan sulfate to anticoagulant forms. HS3ST2 exhibits an atypical subcellular localization at the plasma membrane, where it associates with syndecan-2, rather than being confined to the Golgi apparatus 1. This positioning suggests HS3ST2 participates in cell-surface processes distinct from other 3-O-sulfotransferases. HS3ST2 dysfunction is implicated in multiple disease contexts through epigenetic silencing. In breast cancer, HS3ST2 reexpression via methylation reversal promotes invasiveness in high-invasive cell lines through MAPK and Tcf4-dependent upregulation of matrix metalloproteinases and cadherins 2. Conversely, HS3ST2 promoter hypermethylation occurs in cervical, endometrial, and gastric cancers, serving as a predictor of malignant progression 3, 4, 5. Recent evidence indicates that miR-100–mediated suppression of HS3ST2 promotes endometriosis by increasing endometrial stromal cell proliferation and epithelial-mesenchymal transition 6. In Alzheimer's disease, HS3ST2 overexpression drives cell-autonomous tau aggregation and abnormal phosphorylation, linking heparan sulfate metabolism to neurodegeneration 7. In atherosclerotic plaques, HS3ST2+ macrophages with proinflammatory M1 features were associated with cerebrovascular events 8.