Excessive force-induced root resorption depends on macrophage YAP activation

Excessive force-induced root resorption (RR) during orthodontic treatment represents a pathological consequence of aberrant mechanical loading, yet the mechano-immune mechanisms linking mechanical cues to hard-tissue destruction remain unclear. In this study, we found that, among various immune cell populations in periodontal tissues, macrophages exhibited sustained activation in response to excessive mechanical loading, accompanied by persistent activation of Hippo-YAP signaling. Besides, myeloid-specific deletion of Yap1 in Yap1 ^flox/flox ; Lyz2 -Cre mice significantly reduced excessive force-induced RR compared with Yap1 ^flox/flox controls, and pharmacological inhibition of YAP alleviated RR severity in vivo and inhibited odontoclast/osteoclast differentiation in vitro under excessive force. Moreover, transcriptomic analysis identified the Hippo signaling pathway as a key regulatory mechanism in force-stimulated macrophages, with its effector YAP displaying markedly enhanced nuclear localization both in vivo and in vitro . In parallel, bone marrow-derived macrophages isolated from Yap1 ^flox/flox ; Lyz2 -Cre mice displayed markedly impaired odontoclast/osteoclast differentiation upon mechanical stimulation, supporting a critical role of myeloid YAP in force-induced RR. Mechanistically, excessive force activated YAP nuclear localization in macrophages and regulated odontoclast/osteoclast differentiation via suppressor of cytokine signaling 3 (SOCS3). Collectively, these findings uncover a macrophage-centered mechano-immune mechanism underlying excessive force-induced RR and suggest that targeting macrophage YAP signaling may provide a promising therapeutic strategy for the clinical management of RR.