HS3ST4 (heparan sulfate-glucosamine 3-sulfotransferase 4) is a sulfotransferase that catalyzes the transfer of a sulfo group to N-unsubstituted glucosamine residues on heparan sulfate (HS) chains, utilizing 3'-phospho-5'-adenylyl sulfate as a cofactor 1. Unlike the structurally related HS3ST1 isoform, HS3ST4 does not convert non-anticoagulant heparan sulfate to anticoagulant forms. HS3ST4 participates in HS biosynthetic maturation through catalysis of the rare 3-O-sulfation modification 1. Mechanistically, HS3ST4 expression enhances cytotoxicity and fusogenic activity following varicella-zoster virus (VZV) infection through interaction with VZV glycoproteins, though without affecting viral genome replication 2. Disease relevance encompasses multiple contexts: genetic variants in HS3ST4 associate with post-herpetic neuralgia and herpes zoster reactivation 2, cognitive decline in elderly non-demented individuals 3, osteosarcoma prognosis 4, skin aging phenotypes 5, brain iron accumulation in neurodegeneration 6, and breast cancer metabolic stage progression 7. HS3ST4 methylation patterns correlate with placental cadmium exposure in a sex-specific manner and affect cell damage response pathways 8. In cancer contexts, HS3ST4 may function as both a tumor suppressor and promoter depending on cancer phenotype and molecular signature 1, warranting further investigation for therapeutic targeting.