Ferroptosis-mediated osteoclast-osteoblast crosstalk: signaling pathways governing bone remodeling in osteoporosis.

backgroundOsteoporosis is a metabolic bone disease characterized by disruption of bone homeostasis, resulting from an imbalance between osteoblast-mediated bone formation and osteoclast-driven bone resorption. Emerging evidence implicates ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, in this process. Key molecular hallmarks include glutathione peroxidase 4 (GPX4) inactivation and the intracellular generation of unstable hydroxyl radicals and reactive oxygen species (ROS) accumulation. These accumulated ROS further participate in the oxidation of polyunsaturated fatty acids (PUFAs), generating and accumulating lipid peroxides that ultimately compromise cellular membranes and trigger ferroptosis. This review explores the regulatory mechanisms of ferroptosis, elucidating the roles of key signaling molecules, cytokines, and pathways involved in osteoporosis pathogenesis. METHODS AND MATERIALS: This review synthesizes recent advances, delineating core pathways(e.g., Xc-GSH-GPX4 axis, FSP1-CoQ10-NADPH, and DHODH-CoQ10 and key molecules (TFR1, FPN, ALOX15) regulating osteoporosis. We emphasize that ferroptosis dysregulation in osteoblasts and osteoclasts disrupts cellular redox balance, impairing bone microstructure and biomechanical strength, thereby accelerating osteoporosis progression. Mechanistically, iron overload promotes ROS production via the Fenton reaction, inactivates GPX4, and triggers a lipid peroxidation cascade. Targeting ferroptosis represents a novel governing strategy to restore bone homeostasis. We discuss unresolved questions regarding ferroptosis regulation in clinical osteoporosis treatment and outline future prospects involving molecular activators, precision delivery systems, and integration of cutting-edge technologies, providing a theoretical foundation for basic research and clinical applications.