Mitochondrial OXPHOS integrates immunometabolic cascade for bone regeneration via coupled ATP production and ROS homeostasis.

Osteoinductive calcium phosphate ceramics (CaPs) hold great promise for bone repair, yet the metabolic principles governing their efficacy are poorly defined. Here, we identify mitochondrial oxidative phosphorylation (OXPHOS) as an early and indispensable pathway activated specifically by an osteoinductive tricalcium phosphate (TCPS) in material-induced bone formation. Our findings demonstrate that OXPHOS critically governs the M2 macrophage-osteoclast axis for bone formation by regulating both cellular energy supply and reactive oxygen species (ROS) homeostasis. Disrupting either function-by inhibiting OXPHOS (reducing ATP production) or by disrupting ROS balance (including ROS scavenging or accumulation)-uncouples this metabolic-immunological cascade and abrogates bone formation. Our work establishes mitochondrial OXPHOS as a central metabolic hub that integrates bioenergetics with ROS balance to orchestrate material-induced bone formation via M2 macrophage polarization-osteoclastogenesis axis. Consequently, these insights provide a rational basis for therapeutic modulation of the immunometabolic cascade in bone regeneration, via strategies designed to co-activate OXPHOS and fine-tune ROS dynamics.