CHSY1 (chondroitin sulfate synthase 1) is a bifunctional glycosyltransferase that catalyzes chondroitin sulfate chain polymerization through sequential addition of glucuronic acid and N-acetylgalactosamine residues 1. The enzyme functions as a heterodimeric complex with CHPF or CHPF2 cofactors, which primarily provide stabilizing roles while CHSY1 maintains enzymatic activity 1. In skeletal development, CHSY1 negatively regulates osteogenesis through BMP signaling inhibition, maintaining chondrocyte differentiation and extracellular matrix production 2. CHSY1 deficiency reduces matrix production and promotes cartilage hypertrophy markers, exacerbating osteoarthritis progression 2. During neuronal development, astrocyte-derived CHSY1 produces chondroitin sulfate-glycosaminoglycans that inhibit dendritic arborization 3. Clinically, CHSY1 is upregulated in multiple cancers with protumoral effects. In colorectal cancer liver metastasis, CHSY1 promotes CD8+ T cell exhaustion via succinate metabolism activation and PD-L1 upregulation 4. Similar tumor-promoting roles occur in gastric cancer, where CHSY1 knockdown inhibits proliferation and migration 5. Germline CHSY1 loss-of-function mutations cause Temtamy preaxial brachydactyly syndrome, an autosomal recessive disorder with skeletal, craniofacial, and developmental abnormalities 67. CHSY1 translation is regulated by RNA G-quadruplex structures in its 5'-UTR and polyamines 8.