We first found that HPSE and SDC-2 were significantly up-regulated in IC/BPS patients and then found that inhibition of HPSE using OGT2115 resulted in the alleviation of lower urinary tract symptoms in CYP-induced cystitis mice and restored LPS-induced disruption of the leakage barrier of epithelial cells. Here, PPIG is linked to Bartsocas-Papas syndrome 1.