Fibroblast growth factor receptor 1c, 3c, and 4 (FGFR1c/3c/4)

FGFR1c/3c/4 refers to a specific subset of fibroblast growth factor receptors—specifically the 'c' splice variants of FGFR1 and FGFR3, along with FGFR4—that collectively serve as the signaling receptors for the endocrine hormone fibroblast growth factor 23 (FGF23) [4, 7]. These receptors require the presence of the transmembrane protein alpha-Klotho as a co-receptor to form a high-affinity complex capable of binding FGF23 [2, 12]. This receptor system is primarily expressed in the renal proximal tubules and the parathyroid glands, where it plays a critical role in maintaining mineral homeostasis by promoting phosphate excretion and inhibiting the synthesis of active vitamin D (1,25-dihydroxyvitamin D) [4, 6]. Dysregulation of this pathway, often through excessive FGF23 production, leads to phosphate-wasting disorders such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) [6, 9]. Conversely, in chronic kidney disease, elevated FGF23 levels and reduced Klotho expression contribute to secondary hyperparathyroidism and cardiovascular complications [9, 12]. Therapeutic interventions include monoclonal antibodies like burosumab, which targets the FGF23 ligand to prevent receptor activation, and pan-FGFR inhibitors that block the intracellular kinase activity of the receptors themselves [11].

Other names

FGF23 receptor complexFGFR1 isoform cFGFR3 isoform cFGFR4alpha-Klotho-FGFR complex

Modulation of the FGF23-alpha-Klotho-FGFR signaling axis through either ligand sequestration (e.g., burosumab) or direct inhibition of the receptor's tyrosine kinase activity (e.g., pan-FGFR inhibitors), thereby regulating renal phosphate handling and vitamin D metabolism.