Compression force regulates cementoblast mineralization via <scp>S1PR1</scp> /mitophagy axis

Orthodontically induced inflammatory root resorption (OIIRR) poses a significant clinical challenge, as excessive orthodontic force shortens tooth longevity by impairing cementoblast-mediated cementum mineralization and promoting root resorption. Cementoblasts, essential for mineralized cementum formation and resistance to resorption, exhibit altered mechanosensitivity and mechanotransduction under orthodontic force, yet the role of mitophagy in this process remains poorly understood. In this study, we investigated how the S1PR1/mitophagy axis modulates cementoblast mineralization and OIIRR progression. The in vivo orthodontic loading model revealed that heavy compression force triggered OIIRR and impaired cementoblast mineralization along with suppression of mitophagy in cementoblasts by downregulating PINK1 and PARKIN expression. The in vitro experiments further confirmed that heavy compression force increased reactive oxygen species (ROS) levels, disrupted mitochondrial membrane potential (MMP), and inhibited mitophagy in OCCM30 cells, thereby impairing their mineralization capacity. Mechanistically, S1PR1 upregulation activated mitophagy, which in turn restored cementoblast mineralization under heavy compression force. Moreover, pharmacological activation of S1PR1 with SEW2871 alleviated OIIRR in vivo. These findings highlight the pivotal role of the S1PR1/mitophagy axis in maintaining cementoblast function and mineralization under orthodontic force, offering novel insights into the molecular mechanisms underlying OIIRR and suggesting potential therapeutic strategies to prevent OIIRR during orthodontic treatment.