Phosphate-regulating neutral endopeptidase (PHEX) (PHEX)

Phosphate-regulating neutral endopeptidase (PHEX) is a zinc-dependent type II integral membrane endopeptidase primarily expressed in osteoblasts and odontoblasts, where it plays a crucial role in regulating bone and tooth mineralization and maintaining systemic phosphate homeostasis[1][2][3][4][5][7]. PHEX enzymatically cleaves small integrin-binding ligand N-linked glycoprotein (SIBLING)–derived ASARM peptides, thereby regulating their activity and indirectly controlling the transcription and bioactivity of fibroblast growth factor 23 (FGF23), a phosphatonin that modulates renal phosphate handling[1][2][5]. Loss-of-function mutations in the PHEX gene cause X-linked hypophosphatemia (XLH), the most common hereditary form of hypophosphatemic rickets, leading to elevated FGF23, increased renal phosphate wasting, hypophosphatemia, and defective skeletal mineralization[2][3][4][5][7]. Over 200 pathogenic mutations have been identified, involving nonsense, missense, frameshift, and splicing defects[3][5][7]. While direct drug targeting of PHEX itself is not yet established clinically, XLH patients benefit from agents targeting downstream FGF23, such as Burosumab[7].

Other names

Phosphate regulating endopeptidase X-linkedPhosphate-regulating neutral endopeptidase PHEXPEXHYPHPDR1HYP1XLHMetalloendopeptidase homolog PEXVitamin D-resistant hypophosphatemic rickets proteinX-linked hypophosphatemia proteinPHEX peptidasePhosphate regulating endopeptidase homolog X-linkedLXHR

Restoration of phosphate homeostasis by neutralizing FGF23 (for drugs like Burosumab used in XLH patients with PHEX mutation); Enhancement of renal phosphate reabsorption and improvement of bone mineralization