Abstract
BACKGROUND: Depression plays a crucial role in lung adenocarcinoma (LUAD) occurrence, progression, and prognosis. However, the impact of depression-related genes (DRGs) on the prognosis of LUAD patients is unclear. Thus, a prognosis prediction model was constructed to assess the potential impact of depression on LUAD prognosis. METHODS: The gene expression profiles from The Cancer Genome Atlas (TCGA)-LUAD and GSE68465 were collected for model training and validation. By identifying the intersection of DRGs and differentially expressed genes (DEGs) in LUAD, a risk score model was constructed to stratify patient risk based on univariate and multivariate analyses. The immune infiltration status and therapeutic potential of different risk groups were further explored. The correlation between key genes and clinical outcomes was evaluated in Kaplan-Meier (KM) analysis. Finally, the expression and mechanism of key genes were verified by in vitro experiments. RESULTS: We identified 2,222 DEGs and 385 DRGs-DEGs, and DRGs-DEGs were closely related to nervous system function and cell signaling. Nine DRGs-DEGs were identified to construct the risk score model for risk stratification. The model's predictive accuracy for patient survival was confirmed by receiver operating characteristic (ROC) curve analysis. LUAD patients with high-risk had significantly higher levels of CD8 T cells, B cells memory, and macrophages M1, which may affect the prognosis of LUAD patients. Furthermore, low-risk patients responded better to immunotherapy. KM analysis revealed that ACSS3 was significantly associated with poor prognosis in LUAD patients. oe-ACSS3 inhibits LUAD cell proliferation, migration, and invasion, and also promotes apoptosis. CONCLUSIONS: The nine-gene risk score model proposed in our study demonstrated promising prognostic performance, highlighting the significant role of depression in LUAD prognosis. ACSS3 was demonstrated to play a critical role in regulating LUAD progression and may be a potential therapeutic target for LUAD treatment.