Multi-Omics Research Combined With Experimental Verification to Identify Potential Targets for Temporomandibular Joint Osteoarthritis

Background: Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative joint disease characterized by cartilage destruction and subchondral bone remodeling. However, its molecular mechanisms remain incompletely understood, and effective therapeutic targets are still limited. This study aimed to identify candidate targets for TMJ OA through an integrated multi-omics strategy combined with experimental validation. Methods: Multi-layer omics data including expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL) and molecular quantitative trait loci (mQTL) were merged with TMJ OA Genome-Wide Association Study (GWAS) summary stats. Mendelian Randomization (MR) and colocalization analyses were performed to determine whether there was a causal relationship between the genes. The main results were further validated by immune infiltration analysis, pathway enrichment (Gene Set Enrichment Analysis, GSEA), transcription factor and miRNA network analysis, drug prediction (Connectivity Map, CMap), and molecular docking. A rat forced mandibular retrusion (FMR) model was used for in vivo experimental validation. Results: haloacid dehalogenase like hydrolase domain containing 3 (HDHD3) and high mobility group 20B (HMG20B) were prioritized as candidate genes associated with TMJ OA. Colocalization analysis supported shared signals between TMJ OA and the pQTLs of HDHD3 and HMG20B. Transcriptomic validation showed that HDHD3 was significantly upregulated in the diseased group (p < 0.05). Pathway analyses suggested that HDHD3 was associated with glycolysis- and lactylation-related alterations. In the animal model, mechanical stress significantly increased HDHD3 expression and lactylation-related signals (p < 0.05) and was accompanied by cartilage and subchondral bone damage. Folic acid was identified as a candidate compound through drug prediction and molecular docking. Conclusion: This study provides multi-omics and experimental evidence suggesting that HDHD3 and HMG20B are candidate genes associated with TMJ OA. Notably, HDHD3 may be involved in glycolysis- and lactylation-related alterations during TMJ OA progression. Folic acid was identified as a candidate compound, but its therapeutic relevance requires further validation.