Targeting the immune-metabolic axis reverses orthodontics-induced systemic pathology.

Orthodontic treatment corrects various craniofacial malformations primarily through triggering active alveolar bone remodeling, however the potential impacts of this intervention on the systemic immune state have long been insufficiently explored. Here, we show that mechanical force applied during orthodontic treatment can trigger systemic inflammation dominated by adaptive immune responses. This response not only impairs bone repair at distant body sites but also causes temporary liver dysfunction resembling autoimmune conditions characterized by the expansion of CD69⁺ B cells. Mechanistically, IgM produced by these activated B cells acts as a key pathogenic driver of systemic pathology. Inhibiting the activation of local B cells effectively reversed this immunopathology, underscoring the central role of B cell-derived IgM. We also verified that Piezo1⁺ macrophages function as vital mechanosensors, linking orthodontic mechanical stimulation to B cell activation and subsequent IgM release. Multi-organ metabolomic profiling revealed significant amino acid metabolic dysregulation, which further aggravated systemic inflammation. Crucially, supplementation with lysine and alanine alleviated orthodontic treatment-induced inflammation, restored liver function and promoted distal bone repair. Together, these findings uncover an unrecognized systemic immune-metabolic axis during orthodontic therapy and suggest that targeting B cell-IgM responses or metabolic dysregulation may provide therapeutic opportunities to enhance treatment safety and outcomes.