HS6ST2 is a heparan sulfate 6-O-sulfotransferase that catalyzes the transfer of sulfate from PAPS to the N-sulfoglucosamine residue of heparan sulfate proteoglycans, localizing to the Golgi membrane 1. This enzyme is predominantly expressed in brain tissue and plays critical roles in multiple physiological and pathological processes. In the central nervous system, HS6ST2 is essential for normal cognitive function and memory. Knockout of Hs6st2 in mice decreases HS 6-O-sulfation levels, impairs dendritic spine morphology in hippocampal CA1 neurons, disrupts hippocampal transcriptome expression in dendrite and synapse pathways, and causes memory deficits that recapitulate patient symptoms 1. A pathogenic HS6ST2 mutation (c.916G>C, G306R) affecting the substrate binding site was identified in male twins with X-linked intellectual disability, severe myopia, and mild facial dysmorphisms, with in-vitro studies confirming significantly reduced enzymatic activity 2. Outside the brain, HS6ST2 dysregulation associates with cancer and cartilage pathology. HS6ST2 upregulation promotes cervical cancer cell proliferation, migration, and invasion; high expression correlates with lymph node metastasis and poor survival outcomes 3. Conversely, HS6ST2 downregulation occurs in osteoarthritis and Kashin-Beck disease, where it suppresses chondrocyte viability and impairs aggrecan metabolism 4, potentially through miR-23b-3p-mediated regulation and p38 MAPK pathway activation 5. Pan-cancer analysis reveals HS6ST2 functions as a prognostic marker across multiple malignancies through effects on tumor immunity and drug resistance 6.