Hesperidin from citrus peel ameliorates osteoporosis by suppressing FGF23 via the PI3K/AKT/FOXO1 pathway

As a major citrus flavonoid, hesperidin (HP) shows bone-protective potential, yet its role in calcium–phosphorus homeostasis and antioxidant mechanisms remains unclear. This study investigated the anti-osteoporotic effects of HP in retinoic acid (RA)-induced osteoporotic mice and primary bone marrow mesenchymal stem cells (BMSCs). HP promoted BMSC proliferation, migration, and osteogenic differentiation, with increased alkaline phosphatase (ALP) activity and mineralization. Network pharmacology identified antioxidant PI3K/AKT/FOXO1 pathways as key targets, with fibroblast growth factor 23 (FGF23) as a pivotal effector. In osteoporotic mice, HP normalized serum calcium, phosphorus, and 25-hydroxyvitamin D, increased bone formation and decreased resorption markers, alleviating bone loss and preserving trabecular microarchitecture and enhancing biomechanical properties. Mechanistically, PI3K/AKT/FOXO1-mediated FGF23 suppression was essential for osteoprotection, as confirmed using a PI3K inhibitor. Collectively, these findings suggest that HP ameliorates RA-induced osteoporosis by restoring calcium–phosphorus homeostasis via PI3K/AKT/FOXO1-dependent FGF23 inhibition, underscoring its potential as a functional food ingredient.