CHPF2 (chondroitin polymerizing factor 2) is a glucuronosyltransferase that transfers glucuronic acid from UDP-GlcUA to N-acetylgalactosamine residues on elongating chondroitin polymer chains 1. However, recent structural analysis reveals CHPF2 primarily plays a stabilizing role within heterodimeric complexes (CHSY1-CHPF2 and CHSY3-CHPF2) rather than serving as the catalytic enzyme; only CHSY1 and CHSY3 demonstrate bifunctional glycosyltransferase activities 1. CHPF2 is enriched in astrocytes and regulates chondroitin sulfate glycosaminoglycan biosynthesis, with astrocyte-derived chondroitin sulfate inhibiting neuronal dendritic development and plasticity 23. Beyond its canonical enzymatic role, CHPF2 exhibits a moonlighting function independent of enzymatic activity: upon TNF stimulation, MEK phosphorylates CHPF2 at T588, enabling interaction with TAK1 and IKKα to amplify NF-κB signaling and promote colorectal cancer cell proliferation and metastasis 4. CHPF2 is dysregulated in multiple cancers, serving as a biomarker in hepatocellular carcinoma and bladder cancer with prognostic significance 56. Additionally, variants in CHPF2 accumulate in thrombotic storm patients, suggesting roles in regulating endothelial coagulation control 7. Exosomal lncRNA DUXAP8 regulates CHPF2 expression in intracranial aneurysm pathogenesis 8.