ACAN encodes aggrecan, a major extracellular matrix proteoglycan that functions primarily to resist compression in cartilage by binding avidly to hyaluronic acid via its N-terminal globular domain 1. Beyond skeletal tissues, ACAN is produced by notochordal cells, chondrocytes, and other matrix-producing cell types 1, and its expression is regulated by SOX9-mediated transactivation, with acetylation of SOX9 inhibiting ACAN gene expression and nuclear localization 2. Clinical significance of ACAN dysfunction is substantial. Heterozygous ACAN variants cause a spectrum of phenotypes including short stature (average -3.30 SD), early-onset osteoarthritis, brachydactyly, and midfacial hypoplasia, with 314 reported individuals from 105 families harboring such variants 3. Children with ACAN mutations born small for gestational age frequently show advanced bone age maturation 4. Recombinant human growth hormone (rhGH) treatment, often combined with GnRHa, produces significant height improvement in affected pediatric patients 3. ACAN expression decreases progressively during osteoarthritis development, correlating with disease severity 5. Additionally, ACAN gene polymorphisms have been associated with Alzheimer's disease risk 6. YAP/TAZ-mediated regulation of ACAN also contributes to vascular homeostasis, with dysregulation associated with aneurysm development 7.