Roxadustat ameliorates bone microarchitectural deterioration in CKD-MBD rats in association with mitigated systemic micro-inflammation and restored FGF23–Wnt/β-catenin signaling

Elevated FGF23 is associated with bone microarchitectural deterioration in chronic kidney dis-ease-mineral and bone disorder (CKD-MBD). While roxadustat (a HIF-PHI) is established for the treatment of renal anemia, its potential bone-protective effects in CKD-MBD remain unclear. We investigated whether roxadustat ameliorates femoral microarchitectural deterioration in CKD-MBD rats in association with FGF23 downregulation and restoration of Wnt/β-catenin signaling. A CKD-MBD rat model was established by unilateral nephrectomy and adenine gavage, and animals were randomized into sham, model, and roxadustat (50 or 100 mg/kg, three times weekly) groups for 8 weeks. Renal function, hematological indices, calcium-phosphate parame-ters, and femoral microarchitecture were evaluated, and target protein levels (FGF23, FGFR1, DKK1, β-catenin) were assessed by Western blotting and immunohistochemistry. Roxadustat improved renal function, ameliorated the reduction in erythroid parameters, and restored calcium-phosphate homeostasis. Systemically, it mitigated micro-inflammation by reducing serum CRP and hepcidin, and downregulated serum FGF23 levels as well as tissue FGF23 expression in kidney and bone. In conclusion, the bone-protective effect of roxadustat occurs synchronously with systemic micro-inflammation mitigation, FGF23 downregulation, and Wnt/β-catenin signaling restoration. These findings highlight its pleiotropic therapeutic potential in CKD-MBD management, suggesting a synergistic benefit associated with both systemic metabolic recovery and local skeletal regulation.