Abstract
Depression in patients with prostate cancer (PC) has become a significant public health issue. Given the high treatment failure rate and short life expectancy of patients with castration-resistant prostate cancer (CRPC), their risk of developing major depressive disorder (MDD) is significantly increased. However, the exact mechanisms of comorbidity between CRPC and MDD are not yet clear, and there is a lack of standardized intervention strategies to address this clinical issue. This study used bioinformatics methods combined with Mendelian randomization (MR) analysis to explore the molecular mechanisms of CRPC/MDD comorbidity and predict potential therapeutic drugs for this comorbidity. Three hub genes of the comorbidity (AUTS2, AOC1, ANKRD37) were identified, which have excellent diagnostic value in both diseases. AOC1 and ANKRD37 showed prognostic significance in CRPC, and the risk association of AUTS2 with MDD was also validated through MR analysis. The study also found that immune, inflammatory, androgen response pathways are key mechanisms of comorbidity, but the role of apoptosis should not be overlooked. The study further suggested that the JAK/STAT inhibitor WP1066 may be a potential drug for treating CRPC/MDD comorbidity, and this was validated through molecular docking. These findings not only provide a new perspective on the relationship between CRPC and MDD but also offer important clues for the development of treatment strategies.