TXNIP/PINK1 Mitophagy Axis Promotes Th17 and Bone Loss in Diabetic Periodontitis

Introduction and Aims Diabetic periodontitis (DPD) is characterised by severe alveolar bone loss refractory to conventional therapies. Hyperglycaemia drives Th17-mediated inflammation, yet the underlying immunometabolic mechanism remains unclear. This study aimed to elucidate the role of the thioredoxin-interacting protein (TXNIP)/PTEN-induced kinase 1 (PINK1) mitophagy axis in regulating Th17 responses and bone resorption in DPD. Methods DPD was induced in mice via streptozotocin/high-fat diet and Porphyromonas gingivalis lipopolysaccharide (LPS) challenge. Alveolar bone loss was assessed by micro–computed tomography (micro-CT) and tartrate-resistant acid phosphatase staining. Single-cell RNA sequencing of gingival CD4⁺ T cells was reanalysed. Primary CD4⁺ T cells were exposed to high glucose and LPS in vitro. The TXNIP inhibitor SRI-37330 was administered to validate the mechanism via Western blotting, flow cytometry, and mitochondrial function assays. Results DPD progression correlated with TXNIP upregulation and PINK1 downregulation in CD4⁺ T cells, impairing mitophagy and promoting Th17 differentiation. High-glucose/LPS stimulation recapitulated these phenotypes in vitro. Pharmacologic inhibition of TXNIP restored PINK1-mediated mitophagy, suppressed Th17 responses, and significantly attenuated alveolar bone resorption in DPD mice. Conclusion The TXNIP/PINK1 axis is associated with impaired mitophagy and enhanced Th17 responses. Pharmacologic inhibition of TXNIP attenuated alveolar bone resorption in DPD mice. Clinical Relevance This study provides a theoretical basis and identifies potential therapeutic targets for mitigating alveolar bone loss in diabetic periodontitis by modulating the TXNIP/PINK1 mitophagy axis.