HPSE (heparanase) is an endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) in the extracellular matrix, playing crucial roles in immune regulation and disease pathology 1. The enzyme exhibits pH-dependent activity, becoming active under acidic conditions typical of inflammatory environments and tumor invasion 2. HPSE demonstrates broad antiviral activity as an interferon-stimulated gene product, contributing to cellular defense against multiple viral pathogens including hepatitis C virus, yellow fever virus, and HIV-1 3. In cancer contexts, HPSE expression is downregulated in cultured T lymphocytes, and engineered overexpression enhances CAR-T cell tumor infiltration and antitumor activity by improving extracellular matrix degradation 4. The gene contains regulatory elements including enhancer and insulator regions with functional single nucleotide polymorphisms that modulate expression and influence disease susceptibility, particularly acute graft-versus-host disease risk 56. HPSE serves as a biomarker for various conditions, including abdominal aortic aneurysms and pulmonary arterial hypertension 78. In regulatory T cells, HPSE enables access to IL-2 sequestered in the extracellular matrix, supporting immune tolerance mechanisms 1.