Background <p>DLGAP5 is frequently upregulated in human cancers and is associated with tumor progression. However, its biological role, regulatory mechanism, and downstream signaling in lung adenocarcinoma (LUAD) remain unclear.</p> Methods <p>Public databases were used to analyze DLGAP5 expression, diagnostic value, and prognostic significance across cancers, especially in LUAD. Functional assays in LUAD cells and xenograft models were performed to evaluate the effects of DLGAP5 on proliferation, migration, invasion, and tumor growth. Mechanistic studies were conducted to examine cell cycle- and EMT-related proteins, as well as the transcriptional regulation of DLGAP5 by YY1.</p> Results <p>DLGAP5 was significantly upregulated in multiple cancers and showed strong diagnostic value. High DLGAP5 expression predicted poor overall survival and disease-specific survival, and was an independent prognostic factor in LUAD. DLGAP5 knockdown inhibited LUAD cell proliferation, migration, invasion, and tumor growth. Mechanistically, DLGAP5 silencing reduced CDK4 and CDK6 expression and suppressed the Wnt/β-catenin/EMT pathway, as shown by decreased N-cadherin, Slug, Snail, Twist1, and β-catenin, with increased E-cadherin. In addition, YY1 directly bound to the DLGAP5 promoter and positively regulated its expression. YY1 knockdown reduced DLGAP5 expression and impaired LUAD progression.</p> Conclusions <p>DLGAP5 promotes LUAD progression by enhancing cell proliferation, metastasis, and EMT, while YY1 acts as its upstream transcriptional activator. The YY1/DLGAP5 axis may serve as a potential prognostic biomarker and therapeutic target in LUAD.</p>