HS6ST1 encodes heparan sulfate 6-O-sulfotransferase 1, a Golgi-resident enzyme catalyzing 6-O-sulfation of heparan sulfate (HS) glycosaminoglycans by transferring sulfate from PAPS to N-sulfoglucosamine residues. This post-translational modification is critical for proper HS structure and function in extracellular matrix interactions. HS6ST1 plays essential roles in neuronal development, where it regulates GnRH neuron function and puberty timing 1. The gene operates within convergent signaling pathways with FGFR1, likely via transcription factors Sox9/Sox10 and chr2 regulator Chd7, collectively regulating extracellular matrix and chr2-related gene expression 2. HS6ST1-mediated heparan sulfate biosynthesis also enables FGF signaling in breast cancer dormant cells, promoting tumor recurrence 3. Mutations in HS6ST1 cause hypogonadotropic hypogonadism 15 with or without anosmia (Kallmann syndrome), where loss-of-function variants impair GnRH signaling 4. Heterozygous HS6ST1 mutations cause self-limited delayed puberty, showing incomplete penetrance compared to complete HH 1. In cancer biology, HS6ST1 overexpression in cancer-associated fibroblasts promotes cholangiocarcinoma progression and metastasis 5. HS6ST1 downregulation occurs in gliomas, contributing to altered HS biosynthesis 6. Additionally, heme exposure modulates HS6ST1 expression in endothelial cells, affecting glycocalyx integrity and complement activation in thrombotic microangiopathies 7.