Integrative Immunometabolic Mechanisms of Temporomandibular Disorders: A Population, Cellular to Molecular-Level Study

Introduction and aims Temporomandibular joint disorder (TMD) is a prevalent musculoskeletal condition with complex aetiology. Current therapies are limited by an incomplete understanding of its mechanisms. Emerging evidence highlights immunometabolic regulation in TMD, but integrated studies remain scarce. This study aims to dissect immunometabolic pathways in TMD by linking genetic susceptibility, cellular function, and molecular interactions. Methods We employed a multi-omics framework structured into three sequential phases: (1) Mendelian randomization (MR) screened 731 immune cell traits and 1400 plasma metabolites for causal effects on TMD. Significant exposures were advanced into mediation analysis to identify key mediators; (2) cellular-level characterisation​ using single-cell RNA sequencing of TMD tissues to map the microenvironmental expression of metabolite-target genes, complemented by cell-type-specific MR to infer dendritic cell (DC)-specific causal effects; (3) molecular-level validation​ through molecular docking simulations and Bayesian colocalization to test physical interactions and shared genetic bases. Functional enrichment and pseudotime trajectory analyses delineated biological processes and cellular states. Results MR analyses identified 15 immune cell traits and 21 metabolites with causal effects on TMD. The glycerophospholipid 2-stearoyl-GPE (18:0) mediated 29.3% to 29.8% of the protective effect of DC-associated HLA DR expression. Single-cell transcriptomics revealed distinct expression of its target genes (eg, AKT1, LY96, PRKCA). Cell-type-specific MR confirmed their protective effects. Molecular docking demonstrated direct binding between 2-stearoyl-GPE (18:0) and these target proteins, and colocalization supported a shared genetic basis. Functional enrichment and pseudotime trajectory analyses further indicated DCs exhibit a mature, immunoregulatory phenotype enriched in immune activation pathways. Conclusion This study establishes a coherent immunometabolic pathway in TMD, centred on 2-stearoyl-GPE (18:0) and its regulation of DC function via key target proteins. Integrating population-level causality with cellular and molecular validation provides a unified framework linking genetic predisposition to TMD mechanism. These findings highlight novel therapeutic targets for immunometabolic intervention.