Kaempferide alleviates glucocorticoid-induced osteoporosis by targeting ferroptosis through the GSK3β/Nrf-2/GPX4 pathway.

Glucocorticoid-induced osteoporosis (GIOP) is a common complication of long-term glucocorticoid use, with ferroptosis playing a key role in its pathogenesis. This study investigates whether Kaempferide (KF), a flavonoid derived from traditional Chinese medicine, protects against dexamethasone (Dex)-induced osteoblast ferroptosis and bone loss. In vitro, KF treatment enhanced antioxidant capacity, reduced lipid peroxidation and mitochondrial ROS, and promoted osteogenic differentiation in Dex-exposed osteoblasts. In a rat GIOP model, KF preserved distal femoral microstructure as demonstrated by micro-CT and histological analysis. Mechanistically, KF activated the GSK3β/Nrf2/GPX4 signaling pathway, evidenced by increased GSK3β phosphorylation, Nrf2 upregulation, and elevated GPX4 expression; importantly, these protective effects were reversed by the GSK3β agonist DIF-3. Our findings demonstrate that KF alleviates GIOP by inhibiting ferroptosis through activation of the GSK3β/Nrf2/GPX4 axis, suggesting a potential therapeutic strategy for glucocorticoid-related bone damage.