HPSE2 (heparanase-2) is a structurally related but catalytically inactive pseudoenzyme that functions as an endogenous inhibitor of heparanase-1 (HPSE1). Although HPSE2 binds heparin and heparan sulfate (HS) with higher affinity than HPSE1, it lacks heparanase enzymatic activity and instead competes with HPSE1 for substrate binding, effectively suppressing HS degradation 1. HPSE2 is primarily expressed in smooth muscle-containing tissues, particularly the bladder and brain 1. The protein localizes to pelvic ganglia—autonomic relay stations controlling bladder voiding—where it plays a critical role in neurogenic bladder function 2. Clinically, HPSE2 mutations cause urofacial (Ochoa) syndrome, an autosomal recessive disorder characterized by abnormal facial grimacing and severe lower urinary tract dysfunction including incomplete bladder emptying and hydronephrosis 34. Mouse models reveal that Hpse2 mutations result in impaired neurogenic relaxation of bladder outflow tracts, suggesting the disease originates from peripheral autonomic neuropathy 5. Gene therapy using AAV9/HPSE2 successfully restored bladder function in mutant mice, demonstrating therapeutic potential 2. Beyond urofacial syndrome, HPSE2 exhibits protective functions in endothelial cells, where it prevents HPSE1-mediated HS shedding and protects against LPS-induced inflammatory responses 6. Genetic variants in HPSE2 also show protective associations against multiple myeloma progression 7.