COPB1 deficiency triggers osteoporosis with elevated iron stores by inducing osteoblast ferroptosis

This study investigates the role of COPB1 in maintaining bone homeostasis under conditions of iron accumulation and elucidates its contribution to osteoporosis pathogenesis. Proteomic analysis of human bone tissue identified COPB1 as a key factor associated with reduced bone density and elevated iron stores. In vitro and in vivo experiments demonstrated that COPB1 deficiency impairs osteogenic differentiation by inducing endoplasmic reticulum stress and ferroptosis in osteoblasts. Osteoblast-specific COPB1 knockout mice exhibited significant bone loss, compromised microarchitecture, and reduced biomechanical strength. Therapeutic overexpression of COPB1 partially restored bone mass in iron-overload and ovariectomy mouse models, highlighting COPB1 as a potential therapeutic target for iron-associated osteoporosis.