CHSY3 (chondroitin sulfate synthase 3) is a bifunctional glycosyltransferase that catalyzes chondroitin sulfate (CS) chain polymerization by sequentially transferring glucuronic acid and N-acetylgalactosamine residues to elongating CS polymers 1. The enzyme functions as part of heterodimeric complexes with CHPF or CHPF2, where CHSY3 provides catalytic activity while its binding partners stabilize the complex 1. Chain polymerization occurs through a non-processive, distributive mechanism 1. CHSY3 exhibits reduced specific activity compared to CHSY1. In disease contexts, CHSY3 demonstrates opposing roles: elevated expression in gastric cancer correlates with poor prognosis, promotes tumor cell proliferation and migration, and reduces immunotherapy benefit through increased tumor-associated macrophage infiltration 23. Conversely, CHSY3 depletion causes spontaneous intervertebral disc degeneration through disrupted actin-mediated YAP1 signaling in nucleus pulposus cells, highlighting CS's critical role in maintaining tissue homeostasis 4. In lung cancer, CHSY3 downregulation is associated with advanced disease stage and poor prognosis 5. In hepatocellular carcinoma, CHSY3 expression within decorin-expressing stromal cells correlates with better outcomes 6. These findings establish CHSY3 as a context-dependent regulator with potential as a therapeutic target.