FOLH1 (folate hydrolase 1) encodes prostate-specific membrane antigen (PSMA), a 100 kDa type II integral membrane glycoprotein 1. Primary function: FOLH1 catalyzes folate hydrolysis and exhibits dipeptidyl-peptidase IV-type activity, playing crucial roles in intestinal folate absorption and L-glutamate biosynthesis through carboxypeptidase and peptidase activities. Mechanism: FOLH1 protein localizes to the plasma membrane and cell surface where it binds tetrahydrofolyl-poly(glutamate) polymers, facilitating folate metabolism and glutamate receptor signaling. Disease relevance: FOLH1 is dramatically overexpressed in prostate cancer, with expression levels correlating with tumor aggressiveness 2. High FOLH1 expression associates with AR signaling activation and correlates with neoangiogenesis in renal cell carcinoma, predicting response to tyrosine kinase inhibitors 3. Conversely, FOLH1 polymorphisms influence neural tube defect susceptibility; the rs202676 variant shows protective effects while rs1801133 increases risk 4. Clinical significance: FOLH1 serves as a theranostic target in prostate cancer, enabling both diagnostic imaging via [68Ga]Ga-PSMA and [18F]F-PSMA PET/CT and therapeutic delivery of β-emitter [177Lu]Lu-PSMA-617 for metastatic castration-resistant prostate cancer 5. FOLH1-high metastatic tumors demonstrate improved overall survival (31.9 vs 23.3 months) 6, establishing FOLH1 expression as a prognostic and predictive biomarker.