Major depressive disorder and Hashimoto's thyroiditis: Shared immunometabolic signatures revealed by integrative transcriptomics.

Major depressive disorder (MDD) and Hashimoto's thyroiditis (HT) frequently co-occur, yet their shared molecular underpinnings remain unclear. We performed an integrative transcriptomics analysis combining transcriptomic profiling, immune cell deconvolution, weighted gene co-expression network analysis (WGCNA), and machine learning to identify common immunometabolic signatures in MDD and HT. We first detected 180 co-susceptibility genes dysregulated in both conditions and found these to be enriched in immune-activating signaling, nitric oxide metabolism, oxidoreductase functions, and key KEGG (Kyoto Encyclopedia of Genes and Genomics) pathways such as atherosclerosis and T-cell receptor signaling. Single-sample GSEA (Gene Set Enrichment Analysis) revealed that activated dendritic cells and macrophages are consistently expanded in both diseases. WGCNA linked 2122 HT genes and 1716 MDD genes to these cell types, with seven genes overlapping the co-susceptibility set. LASSO regression and random forest then refined five feature genes-SUCNR1, MORF4L2, FAM198B, MMP9, and PLTP-which were validated across discovery and validation cohorts. Correlation analysis highlighted strong associations between MMP9 and macrophages, and between MORF4L2 and dendritic cells. A five-gene nomogram for MDD achieved an AUC of 0.75, while molecular docking suggested succinic acid as a dual-target candidate. Together, our findings propose novel biomarkers and therapeutic targets that bridge thyroid autoimmunity and neuroinflammation.