成纤维细胞生长因子23（FGF23）是肿瘤性骨软化症（TIO）致获得性低磷血症和骨软化症的核心分子。目前，FGF23代谢调控机制尚不明确。作为FGF23水平升高最显著的获得性低磷血症，TIO为深入探索机体FGF23正向调控机制提供了绝佳的天然模型。研究表明FGF23的O-GalNAc糖基化可促进FGF23的分泌，本团队前期TIO转录组研究亦发现，肿瘤组织中编码O-GalNAc糖基化酶的基因GALNT3表达显著上调。据此提出：GALNT3对FGF23的O-GalNAc糖基化修饰是TIO中FGF23代谢异常的主要原因。本课题拟在TIO中通过转录组研究、离体实验（TIO肿瘤原代细胞培养与细胞模型建立）及在体动物实验（TIO PDX小鼠模型），深入阐明GALNT3对FGF23的调控作用，并初步探索抑制GALNT3表达对TIO的治疗作用，有望揭示TIO的致病机制，为靶向治疗的开展和预后判断提供依据。

Fibroblast growth factor 23 (FGF23) is the key factor in the pathogenesis of hypophosphatemia and rickets arising from tumor induced osteomalacia (TIO). The exact underlying mechanisms resulting in FGF23 dysregulation in many disorders remain to be elucidated. As the acquired condition of hypophosphatemia with the most prominent FGF23 elevation, TIO provides an ideal model for the study of the FGF23 up-regulation pathway. It has been reported that O-glycosylation of FGF23 could increase its secretion. Our previous transcriptomic analysis has also proven that the expression of GALNT3, the gene coding for the polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-T3), the enzyme mediating the O-glycosylation of FGF23, is markedly elevated in patients with TIO. We thus propose that the increased O-GalNAc glycosylation of FGF23 mediated by GALNT3 is the key factor driving FGF23 overproduction in TIO patients. This project aims to illuminate the role of GALNT3 in FGF23 dysregulation in TIO through a combination of transcriptomics analysis, in vitro ( primary TIO tumor cells and established cell models ) and in vivo ( established TIO patient-derived xenograft mouse models ) studies. Inhibition of GALNT3 will also be performed in animal models to explore the possible therapeutic effects. The elucidation of FGF23 metabolism in TIO will reveal the underlying mechanism of the disease pathogenesis and provide new clues for developing targeted therapy and predicting prognosis in patients with TIO.