Emerging Roles of FGFR3 and FGF23-Associated Signaling in Renal Fibrosis: Molecular Integration, Clinical Correlates, and Therapeutic Perspectives
- 1Jilin Medical University, Jilin 132013, China
- 2National Engineering Research Center of Cell Growth Factor Drugs and Protein Preparations (Jilin Center), Jilin 132013, China
- 3Jilin Jinuo Biological Engineering Co., Ltd., Changchun 130600, China
Abstract
Renal fibrosis represents the final common pathway of chronic kidney disease (CKD) progression and remains a major therapeutic challenge. Fibroblast growth factor receptor 3 (FGFR3) has emerged as a context-dependent component of fibroblast growth factor (FGF) signaling, but its renal role remains incompletely defined because direct receptor-specific evidence is scarce. This review integrates kidney-specific FGFR3 studies with endocrine FGF23–Klotho biology and broader FGF/FGFR networks using an explicit evidence hierarchy. Current direct renal evidence is limited to two 2025 experimental studies: an FGF18-associated FGFR3–AMPK–NOX4 program that attenuated folic acid-induced fibrosis, and a single toxicant model reporting an FGF9–FGFR3–PI3K/Akt program associated with fibroblast proliferation. The latter requires independent replication before generalization beyond toxicant nephropathy. By contrast, physiological renal FGF23 signaling is best established through FGFR1c–α-Klotho, whereas the strongest evidence for Klotho-independent pathological FGF23 signaling involves FGFR4 in cardiovascular tissues; direct evidence that FGF23 promotes renal fibrosis specifically through FGFR3 is lacking. Accordingly, FGFR3 should be viewed as an emerging, ligand- and compartment-dependent signaling component rather than a validated CKD therapeutic target. Future priorities include human kidney spatial and phosphoproteomic profiling, cell-specific FGFR3 perturbation, longitudinal FGF23/Klotho biomarker studies, and mechanism-based evaluation of FGFR-directed strategies with integrated renal and mineral-metabolism endpoints.
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BibTeX
@article{fu2026emerging,
title = {{Emerging Roles of FGFR3 and FGF23-Associated Signaling in Renal Fibrosis: Molecular Integration, Clinical Correlates, and Therapeutic Perspectives}},
author = {Ying Fu and Hengping Wang and Lei Wang and Huiyan Wang},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101431},
url = {https://www.mdpi.com/2218-273X/16/10/1431},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Emerging Roles of FGFR3 and FGF23-Associated Signaling in Renal Fibrosis: Molecular Integration, Clinical Correlates, and Therapeutic Perspectives
AU - Ying Fu
AU - Hengping Wang
AU - Lei Wang
AU - Huiyan Wang
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101431
UR - https://www.mdpi.com/2218-273X/16/10/1431
AB - Renal fibrosis represents the final common pathway of chronic kidney disease (CKD) progression and remains a major therapeutic challenge. Fibroblast growth factor receptor 3 (FGFR3) has emerged as a context-dependent component of fibroblast growth factor (FGF) signaling, but its renal role remains incompletely defined because direct receptor-specific evidence is scarce. This review integrates kidney-specific FGFR3 studies with endocrine FGF23–Klotho biology and broader FGF/FGFR networks using an explicit evidence hierarchy. Current direct renal evidence is limited to two 2025 experimental studies: an FGF18-associated FGFR3–AMPK–NOX4 program that attenuated folic acid-induced fibrosis, and a single toxicant model reporting an FGF9–FGFR3–PI3K/Akt program associated with fibroblast proliferation. The latter requires independent replication before generalization beyond toxicant nephropathy. By contrast, physiological renal FGF23 signaling is best established through FGFR1c–α-Klotho, whereas the strongest evidence for Klotho-independent pathological FGF23 signaling involves FGFR4 in cardiovascular tissues; direct evidence that FGF23 promotes renal fibrosis specifically through FGFR3 is lacking. Accordingly, FGFR3 should be viewed as an emerging, ligand- and compartment-dependent signaling component rather than a validated CKD therapeutic target. Future priorities include human kidney spatial and phosphoproteomic profiling, cell-specific FGFR3 perturbation, longitudinal FGF23/Klotho biomarker studies, and mechanism-based evaluation of FGFR-directed strategies with integrated renal and mineral-metabolism endpoints.
SN - 2218-273X
ER -