HS6ST3 (heparan sulfate 6-O-sulfotransferase 3) is a Golgi-resident sulfotransferase enzyme that catalyzes 6-O-sulfation of heparan sulfate by transferring sulfate from PAPS to the N-sulfoglucosamine residue 1. The enzyme undergoes beta-secretase-regulated proteolytic processing and can be secreted extracellularly, with intracellular activity directly controlling heparan sulfate 6-O-sulfation levels 2. HS6ST3 is differentially expressed across tissues and dysregulated in multiple disease contexts. In breast cancer, HS6ST3 upregulation promotes tumor growth, migration, and invasion through IGF1R signaling and XAF1 suppression; silencing HS6ST3 inhibits these processes 3. Genetically, HS6ST3 polymorphisms associate with obesity and elevated triglycerides with gender-specific effects 1, and variants show associations with diabetic retinopathy risk in type 2 diabetes 4. Gene-based analysis identified HS6ST3 as significant for clinical duration modulation in sporadic Creutzfeldt-Jakob disease 5. Additionally, HS6ST3 is implicated in coronary artery disease susceptibility through transcriptome-wide association analysis 6, and HBV integration into the HS6ST3 locus occurs in fibrosis-related contexts 7. These findings establish HS6ST3 as a multifunctional enzyme relevant to metabolic, vascular, neurodegenerative, and neoplastic diseases.