GALNT3 encodes polypeptide N-acetylgalactosaminyltransferase 3, an enzyme that catalyzes the initial step in O-linked glycosylation by transferring N-acetyl-D-galactosamine to serine or threonine residues on target proteins 1. The enzyme's primary function involves post-translational modification of key substrates including fibroblast growth factor 23 (FGF23), where GALNT3-mediated O-glycosylation prevents proteolytic cleavage and enables secretion of biologically active intact FGF23 1. This mechanism is crucial for phosphate homeostasis, as FGF23 regulates blood phosphate levels by inhibiting renal phosphate reabsorption and vitamin D synthesis 2. GALNT3 expression is regulated by the FGFR1c-MEK/ERK signaling pathway in response to high phosphate levels, forming a feedback mechanism for phosphate sensing 3. Disease relevance includes hyperphosphatemic familial tumoral calcinosis caused by GALNT3 deficiency, and associations with osteoporosis where reduced GALNT3 expression correlates with decreased bone mineral density 45. Additionally, GALNT3 has been implicated in male infertility and cancer progression, including intrahepatic cholangiocarcinoma where it promotes metastasis 67. The enzyme's role in FGF23 regulation makes it clinically significant for understanding and treating phosphate homeostasis disorders 2.