The Pathophysiological Functions of Heparanases: From Evolution, Structural and Tissue‐Specific Perspectives

Heparanase 1 (HPSE1) is a unique endoglycosidase responsible for the enzymatic cleavage of heparan sulfate, thereby playing important functions in cancer processes. In contrast, the structurally related Heparanase 2 (HPSE2) lacks catalytic activity and appears to counteract HPSE1 activities. However, contradictory observations in various pathologies highlight the need for a better understanding of the respective contributions of both heparanases. In this review, we provide a comprehensive resource about the biology of HPSE1 and HPSE2 based on findings from different mouse models, with an emphasis on immune cells and their involvement in skin pathophysiology. In addition, we explore the evolutionary relationships between the two heparanases and describe the structure-function of HPSE2 using the advanced protein-prediction tool AlphaFold 3 (AF3). These approaches unveil new insights for deciphering the functional molecular determinants that distinguish HPSE1 from HPSE2.