HSPG2 (heparan sulfate proteoglycan 2), also known as perlecan, is a large modular extracellular matrix proteoglycan that plays critical roles in tissue structure and development. The protein functions as a basement membrane component with anti-angiogenic properties requiring calcium ion binding for full activity [UniProt]. HSPG2 promotes structural and functional maturation of cardiomyocytes by regulating extracellular matrix organization and metabolic processes, likely through binding to the dystroglycan complex 1. During wound healing and tissue regeneration, HSPG2 expression is activated to reestablish tissue boundaries and basement membranes 2. HSPG2 also participates in fibrosis regulation through the TNFSF13/HSPG2 signaling pathway, which activates NF-κB signaling and controls fibroblast proliferation and migration 34. The gene is highly conserved evolutionarily, present in placozoans, cnidarians, and bilaterians, reflecting its ancient role in differentiating cell types separated by acellular matrices 2. HSPG2 mutations and haploinsufficiency are associated with multiple clinical conditions including Schwartz-Jampel syndrome, dyssegmental dysplasia Silverman-Handmaker type, 1p36 deletion syndrome, Balkan endemic nephropathy, and diabetic nephropathy 5678. These associations highlight HSPG2's importance in basement membrane integrity, tissue organization, and pathological processes involving fibrosis and metabolic dysfunction.