PHOSPHO1 (phosphoethanolamine/phosphocholine phosphatase 1) is a cytosolic phosphatase that catalyzes hydrolysis of phosphoethanolamine (PEA) and phosphocholine (PCho) with high specific activity 1. The enzyme exhibits Mg2+-dependent activity with optimal function at pH 6.7, and also possesses phospholipase C activity toward phosphatidylcholine and phosphatidylethanolamine 2. PHOSPHO1 serves dual roles in bone mineralization and metabolic regulation. During skeletal development, PHOSPHO1 generates inorganic phosphate within matrix vesicles to initiate hydroxyapatite crystallization, functioning non-redundantly with TNAP/ALPL 3. Beyond mineralization, PHOSPHO1 regulates systemic energy metabolism: Phospho1-/- mice exhibit improved glucose homeostasis and resist high-fat-diet-induced obesity and diabetes, with mechanisms involving reduced serum choline levels and altered osteoblast gene expression 4. PHOSPHO1 also suppresses ferroptosis in retinal pigment epithelial cells by reducing phosphatidylethanolamine levels and intracellular iron accumulation, suggesting therapeutic potential for age-related macular degeneration 5. In pathological contexts, NR4A3-mediated upregulation of PHOSPHO1 promotes vascular calcification through histone lactylation-dependent transcriptional mechanisms 6. PHOSPHO1 loss-of-function in humans may cause dentoalveolar manifestations resembling pseudohypophosphatasia 3, establishing PHOSPHO1 as a multifunctional enzyme linking bone metabolism to systemic disease processes.