Machine Learning Reveals Common Regulatory Mechanisms Mediated by Autophagy-Related Genes in the Development of Inflammatory Bowel Disease and Major Depressive Disorder

Background: Major Depressive Disorder (MDD) is more common in patients with Inflammatory Bowel Disease (IBD) than in the general population, suggesting a shared but unclear pathogenesis. Autophagy, a conserved intracellular cleaning process, maintains cellular health by removing debris and recycling nutrients. Given the limited research on autophagy in this comorbidity, this study investigated the role of autophagy-related genes in both disorders. Aim: This study aimed to identify shared autophagy-related mechanisms between IBD and MDD and to explore potential therapeutic strategies. Methods: We identified differentially expressed autophagy-related genes (DE-ARGs) in diseased versus normal tissues. Shared DE-ARGs between IBD and MDD were designated Co-DEGs. We analyzed correlations among Co-DEGs and their association with immune cell infiltration. Four machine-learning algorithms were used to pinpoint key biomarkers. Potential therapeutic agents were predicted and validated via molecular docking. Results: We identified 47 shared Co-DEGs. Among these, CASP1 emerged as a cross-disease shared susceptibility-associated gene (SSAG), consistently selected by all machine-learning models. Drug-gene interaction analysis and molecular docking identified compounds that could regulate CASP1. Single-cell analysis suggested CASP1 helps reshape the immune microenvironment in Crohn’s disease. Furthermore, Mendelian randomization identified WDR6 as a shared genetic risk factor for both conditions. Conclusions: Our findings illuminate autophagy-mediated mechanisms linking gut and brain disorders. The identification of CASP1 as a SSAG, along with candidate therapeutics, provides a foundation for future research and targeted treatments for IBD and MDD comorbidity.