Mechanism of YAP‐Mediated Regulation of Osteogenic Differentiation via Cell Adhesion in a Mechanical Stimulus‐Icariin Coupled Environment

ABSTRACT Critical‐sized maxillofacial bone defects remain a major clinical challenge due to the limited osteoinductive capacity of existing biomaterials. While cell adhesion is recognized as an initiating event in bone regeneration, how adhesive interactions integrate biochemical and mechanical cues to regulate osteogenic commitment remains poorly understood. Here, we demonstrate that the synergistic coupling of mechanical stimulation (MS) and icariin (ICA) promotes osteogenic differentiation through the integrin β 1 /β‐actin/YAP signaling axis. By combining single‐cell adhesion force measurements using a robotic micro‐operating system with biomimetic three‐dimensional scaffolds, we show that MS‐ICA coupling enhances osteoblast adhesion, induces actin cytoskeletal remodeling, and facilitates YAP nuclear translocation, thereby activating osteogenic gene expression. Genetic or pharmacological disruption of integrin β 1 , β‐actin, or YAP abrogated the pro‐osteogenic effects, confirming their essential roles in this mechanotransductive pathway. In a rabbit mandibular defect model, ICA‐functionalized scaffolds under physiological loading significantly accelerated bone regeneration. Collectively, these results elucidate a mechanistic link between cell adhesion and lineage specification and establish a design principle for biomaterials that integrate mechanical and biochemical regulation to enhance bone regeneration.