DKK1 Overexpression in Lung Adenocarcinoma: Prognostic Implications, Immune Microenvironment Correlates, and Regulatory Network Characterization

Lung adenocarcinoma (LUAD) is a prevalent malignancy with poor survival outcomes, underscoring the need for better biomarkers and therapeutic targets. Dickkopf-1 (DKK1), a secreted Wnt pathway inhibitor, is dysregulated in many cancers and can promote tumor progression and immune evasion. This study aimed to investigate DKK1 expression and its clinical, immunological, and molecular significance in LUAD. Transcriptomic and clinical data from TCGA and GTEx were analyzed to evaluate DKK1 expression, prognostic relevance, immune infiltration, and associated pathways. Functional enrichment and co-expression networks were constructed in silico. Key findings were validated in vitro using siRNA-mediated DKK1 knockdown in lung cancer cells, followed by assays of proliferation, migration/invasion, apoptosis, cell cycle, and protein expression. DKK1 was significantly overexpressed in LUAD and correlated with advanced stage and poor survival. Enrichment analyses suggested roles in extracellular matrix remodeling and invasion. High DKK1 expression was also associated with increased infiltration of innate immune cells and elevated PD-L1 expression, indicating a potential role in shaping an immunosuppressive microenvironment. Functional experiments further confirmed that DKK1 knockdown reduced proliferation, impaired migration and invasion, induced cell-cycle arrest, and promoted apoptosis in LUAD cells. DKK1 serves as a strong prognostic biomarker in LUAD, linking high expression to aggressive clinicopathologic features and immunosuppressive microenvironments. Its knockdown reversed malignant phenotypes in vitro, supporting DKK1 as a potential therapeutic target and a predictor of immunotherapy resistance.