EXTL2 is a glycosyltransferase that functions as an alpha-1,4-N-acetylhexosaminyltransferase involved in heparan sulfate (HS) biosynthesis 1. Unlike EXT1/EXT2 which form a polymerase for continuous HS chain elongation 2, EXTL2 acts as a negative regulator by transferring N-acetylglucosamine (GlcNAc) residues to phosphorylated tetrasaccharide linkage regions, terminating chain elongation 2. The enzyme is ubiquitously expressed across tissues and during early embryonic development 1. EXTL2 maintains tissue homeostasis under pathological conditions. EXTL2-knockout mice exhibit elevated glycosaminoglycan production and impaired liver regeneration following chemical-induced liver failure due to reduced hepatocyte-growth-factor signaling 2. Additionally, EXTL2 loss enhances vascular calcification through altered bone-morphogenetic-protein signaling in vascular smooth muscle cells 2. In gastric cancer, EXTL2 deletion increases heparan sulfate levels and Syndecan-4 expression, promoting aggressive cellular phenotypes including enhanced motility and invasion 3. Clinically, EXTL2 dysfunction associates with multiple diseases. Reduced EXTL2 expression occurs in osteoarthritis and Kashin-Beck disease cartilage, correlating with impaired chondroitin sulfate synthesis and cartilage damage 4. Genome-wide association studies identified EXTL2 variants associated with asthma exacerbations across multi-ancestry populations 5. EXTL2 targeting via RNA interference shows therapeutic potential for heparan-sulfate-storing mucopolysaccharidoses 6.