PHEX is an X-linked membrane-bound endopeptidase that regulates phosphate homeostasis by cleaving ASARM peptides derived from SIBLING proteins 123. Specifically, PHEX cleaves ASARM peptides between Ser and Glu or Asp residues 3, with critical roles in osteogenic differentiation, bone mineralization, and dentin development through cleavage of MEPE- and DMP1-derived ASARM peptides 23. PHEX also inhibits cathepsin B-mediated MEPE degradation, preventing MEPE clearance 4. Loss-of-function mutations in PHEX cause X-linked hypophosphatemic rickets (XLH), the most common inherited phosphate-wasting disorder 56. PHEX deficiency leads to increased fibroblast growth factor 23 (FGF23) production by osteoblasts and osteocytes, causing renal phosphate wasting, impaired calcitriol synthesis, and lifelong hypophosphatemia 76. Clinical manifestations include rickets, osteomalacia, short stature, dental hypomineralization, and bone deformities in children, with adults developing hyperparathyroidism, enthesopathies, and osteoarthritis 5. Recent therapeutic advances targeting FGF23 with burosumab have substantially improved outcomes, though gene repair approaches are being explored 76.