Background: Lung adenocarcinoma (LUAD) is a major cause of cancer-related mortality worldwide. However, its key driver genes and molecular mechanisms remain insufficiently defined. This study aimed to identify novel oncogenic drivers in LUAD, focusing on leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4). We analyzed transcriptomic data from The Cancer Genome Atlas (TCGA) and developed a prognostic model.

Methods: Differentially expressed genes between LUAD and normal lung tissues were identified using TCGA data. An initial analysis using DESeq2 with a fold-change threshold of ≥4 identified 3100 significantly differentially expressed genes (adjusted p < 0.05; 2671 upregulated and 429 downregulated). Univariate Cox regression (hazard ratio, HR) and least absolute shrinkage and selection operator (LASSO) regression were employed to construct a prognostic risk model, reducing the pool to 28 prognostic genes. Intersecting these with 19 genes both highly expressed and associated with poor prognosis yielded 10 key prognostic markers, including LGR4. Experimental validation was performed: LGR4 mRNA expression was quantified by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in clinical LUAD samples, and functional assays (cell counting kit-8 (CCK-8) proliferation, wound healing, and Transwell migration/invasion) as well as a nude mouse xenograft model were performed to assess the role of LGR4.

Results: In vitro assays demonstrated that LGR4 knockdown significantly suppressed proliferation, migration, and invasion of A549 and H1650 cells (all p < 0.05), whereas LGR4 overexpression in H1299 cells produced the opposite effect (p < 0.05). In vivo, a subcutaneous xenograft model in nude mice further confirmed that LGR4 promotes tumor growth (p < 0.05). Mechanistic analyses revealed that LGR4 activates the nuclear factor kappa-B (NF-κB) signaling pathway, leading to the upregulation of cyclin D1 (CCND1), matrix metalloproteinase 2 (MMP2), and vascular endothelial growth factor (VEGF) (p < 0.05), which regulate cell cycle progression, extracellular matrix remodeling, and angiogenesis, thereby facilitating LUAD progression.

Conclusion: Collectively, these findings demonstrate that LGR4 serves as a novel prognostic biomarker and potential therapeutic target in LUAD. This study provides a theoretical framework for further elucidating the molecular mechanisms underlying lung adenocarcinoma and advancing targeted therapeutic strategies.