摘要Osteoporosis(OP)is characterized by impaired osteoblast activity and excessive bone resorp-tion,yet effective anabolic therapies remain limited.Here,we identify heat shock cognate 71 kDa protein(HSC70)as a novel negative regulator of osteoblast differentiation and reveal echinacoside(ECH),a natural phenylethanoid glycoside from Cistanche deserticola,as its dir-ect inhibitor.Functional studies demonstrated that inhibition or knockdown of Hsc70 pro-moted osteoblast differentiation and mineralization,while Hsc70 overexpression abrogated the effects of ECH.Mechanistically,ECH suppressed HSC70 activity to activate Wnt/β-catenin signaling,enhance β-catenin nuclear translocation,and improve mitochondrial dynamics,ATP production,and biogenesis,thereby providing metabolic support for osteogenesis.In vivo,ECH treatment and hsc70 knockout alleviated glucocorticoid-induced bone loss and re-stored mineralization in zebrafish models.Collectively,this work uncovers the HSC70-β-catenin/mitochondrial axis as a druggable pathway for skeletal homeostasis and positions ECH as a promising natural lead for developing bone-anabolic therapies against OP.