Identification and experimental confirmation of TBC1D10C as a shared transcriptional link between abdominal aortic aneurysm and major depressive disorder

Abdominal aortic aneurysm (AAA) and major depressive disorder (MDD) are prevalent conditions with substantial global health burdens. Growing clinical evidence indicates a close relationship between them, implicating shared pathogenic mechanisms of immune dysregulation and inflammation. Deciphering this molecular interplay is critical, as it may reveal unified therapeutic strategies for these distinct disorders. This study aims to identify such shared molecular pathways, elucidate their co-pathogenesis, and discover novel therapeutic targets with dual relevance. We integrated seven Gene Expression datasets, employing differential expression analysis and weighted gene co-expression network analysis to identify shared modules. Hub genes were prioritized via machine learning and validated using scRNA-seq and murine models. Integrative analysis revealed 100 shared genes. TBC1D10C was identified as a key hub gene and validated across platforms. Immune infiltration and scRNA-seq analysis localized TBC1D10C primarily to B and CD4 + T cells, where its expression inversely correlated with lymphocyte activation. Mouse models of AAA and MDD both exhibited downregulated TBC1D10C. TBC1D10C is a key regulator at AAA and MDD. Its expression shows negative correlation with lymphocyte activation and inflammation. This study provides novel insights into their shared immunopathology and nominates a potential therapeutic target. • TBC1D10C was first identified as a novel shared hub gene for AAA and MDD via multi-omics analysis. • TBC1D10C suppresses shared inflammatory pathways by inhibiting lymphocyte activation. • Reduced TBC1D10C validated in models establishes its pivotal comorbidity link and therapeutic potential.