Abstract / Summary
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.