PHPT1 (phosphohistidine phosphatase 1) is a 14-kDa mammalian enzyme that catalyzes dephosphorylation of phosphohistidine residues on target proteins 1. As the only known mammalian phosphohistidine phosphatase, PHPT1 regulates phosphohistidine levels on proteins involved in signaling, lipid metabolism, and ion transport 2. The enzyme is ubiquitously expressed across tissues with particularly high levels in heart, skeletal muscle, and continuously dividing epithelial cells 3. Mechanistically, PHPT1 directly interacts with substrate phosphorylation sites and modulates downstream signaling cascades; oxidative modification at Met95 does not impair enzymatic function 2. In pulmonary hypertension, PHPT1 acts protectively by negatively regulating TRPV5 signaling in pulmonary artery smooth muscle cells, suppressing pathological proliferation and vascular remodeling 4. Clinically, PHPT1 dysregulation associates with malignancy: elevated PHPT1 expression in lung cancer correlates with advanced stage and lymph node metastasis 5, while high PHPT1 in renal cell carcinoma predicts poor overall survival 6. Additionally, protein-coding variants in PHPT1 contribute to venous thromboembolism risk through coagulation pathway mechanisms 7. These findings position PHPT1 as a potential therapeutic target for vascular and neoplastic diseases.