(1) Abstract: This study reveals the role of the glycolysis–histone lactylation axis in periodontal ligament fibroblasts under mechanical loading. Orthodontic tension promotes the expression of glycolysis-related genes, enhances H3K18la, and enriches it at the CXCL1 promoter, thereby upregulating CXCL1 transcription and secretion and further affecting macrophage polarization and alveolar bone remodeling.

(2) Background: Bone tissue adapts to mechanical force. Alveolar bone is metabolically active, and orthodontics is a mechanical force-driven bone remodeling process. Aseptic immune responses participate in initiating bone remodeling, but the mechanisms remain unclear. Periodontal ligament fibroblasts are major mechanosensing cells and immunomodulatory cells. Mechanical stimuli can regulate glycolysis, and lactate, as a metabolic product, participates in histone lactylation, linking metabolism to epigenetics; however, its role in periodontal ligament fibroblasts remains unclear.

(3) Main Content: The study used an orthodontic tooth movement model and an in vitro stretch model and found that tension activates glycolysis in periodontal ligament fibroblasts and increases H3K18la. CUT&Tag showed that H3K18la is enriched at the CXCL1 promoter and promotes CXCL1 expression. Glycolysis inhibition reduces H3K18la and CXCL1. CXCL1 enhances macrophage oxidative phosphorylation and promotes M2 polarization via CXCR2. In vivo inhibition of glycolysis or blockade of the CXCL1/CXCR2 axis disrupts the immune microenvironment and affects bone formation.

(4) Study Design: In vivo, a mouse orthodontic tooth movement model was established, with control, periodontal injection of the glycolysis inhibitor 3PO, and Cxcr2 knockout groups. In vitro, human periodontal ligament fibroblasts were subjected to cyclic stretch, combined with exogenous lactate and 3PO treatment. Single-cell RNA sequencing, CUT&Tag, RNA sequencing, immunoblotting, immunofluorescence, ELISA, flow cytometry, Seahorse metabolic analysis, micro-CT, and tissue staining were used to analyze metabolism, epigenetics, immunity, and bone remodeling.
(5) Results: Orthodontic tension induces glycolysis in periodontal ligament fibroblasts, with lactate accumulation and enhanced H3K18la. H3K18la is enriched at the CXCL1 promoter and upregulates CXCL1. CXCL1 promotes macrophage oxidative phosphorylation and M2 polarization via CXCR2. In vivo, 3PO inhibits H3K18la and CXCL1, reduces CXCR2-positive macrophage infiltration, and inhibits bone formation. Cxcr2 knockout impairs M2 polarization and tension-side bone deposition. These results indicate that the glycolysis–H3K18la–CXCL1 axis participates in shaping a pro-resolving immune microenvironment and promotes alveolar bone formation.

(6) Future Directions: This study links mechanical force, metabolism, epigenetics, and immunity. Future studies should use cell-type-specific genetic approaches to define the contribution of periodontal ligament fibroblasts, validate findings in a unified single-species platform, and consider local hypoxia, inflammatory status, and other histone modifications. The H3K18la–CXCL1 axis may serve as an important direction for understanding orthodontic bone remodeling, but its local regulation and safety still require further validation.

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