miR-34a-5p accelerates osteoporotic fracture healing by suppressing Foxp1 and modulating hippo/YAP-mediated bone remodeling

• miR-34a-5p represses Foxp1 , rebalancing osteoblast–osteoclast lineage dynamics. • miR-34a-5p attenuates Hippo signaling to elevate YAP activity and reinforce osteogenic commitment. • By integrating Foxp1 suppression with Hippo/YAP pathway, miR-34a-5p accelerates osteoporotic fracture healing. Osteoporotic fracture healing is orchestrated by the dynamic interplay between osteoblasts and osteoclasts, with microRNAs (miRNAs) serving as pivotal regulators of bone metabolism. This study aimed to elucidate the role of miR-34a-5p in osteoporotic fracture repair and its underlying molecular mechanisms. In vitro investigations demonstrated that miR-34a-5p suppresses osteoclast differentiation by directly targeting Foxp1, while concurrently mitigating Foxp1-mediated inhibition of osteoblast differentiation. Transcriptomic profiling of MC3T3-E1 osteoblasts, revealed that miR-34a-5p modulates osteoblast differentiation predominantly via the Hippo/YAP signaling axis, a finding further corroborated by Western blot, underscoring its central role in osteogenic regulation. In an ovariectomized (OVX) mouse femoral fracture model, local administration of miR-34a-5p mimics at the fracture site markedly accelerated bone repair. Micro-CT assessment demonstrated significant enhancement in bone volume and trabecular microarchitecture, while histological evaluations confirmed the expedited progression of bone regeneration. Collectively, these findings establish that miR-34a-5p orchestrates osteoblast and osteoclast activity through Foxp1 targeting and directly promotes osteoblast differentiation via the Hippo/YAP pathway, providing mechanistic insights and identifying potential therapeutic targets for miRNA-based strategies in bone repair. miR-34a-5p promotes osteoporotic fracture healing by targeting Foxp1 , thereby coordinately regulating osteoblast and osteoclast activity. In addition, miR-34a-5p directly modulates osteoblast function through the Hippo/YAP signaling pathway, leading to increased YAP activity and enhanced bone formation.