To construct a prognostic risk model based on multi-omics features and systematically analyze the prognostic value of goblet cell-related adhesion molecules in lung adenocarcinoma (LUAD), providing biomarker references for precision diagnosis and treatment.

This study integrated TCGA-LUAD (n=598), GTEx normal lung tissue (n=110), and three GEO cohorts (GSE31210, etc., n=189) for differential expression analysis. A prognostic model was constructed using LASSO-Cox regression, and the expression of target genes was validated through real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) experiments in the NCI-H1975 cell line.

1 583 differentially expressed genes (|log2FC|>1, FDR<0.05) were identified in LUAD samples, including 883 upregulated and 700 downregulated genes. GO/KEGG analysis revealed that these genes were significantly enriched in cell cycle regulation (GO: 0045786, P=1.4e-07) and the extracellular matrix-receptor(ECM) interaction pathway (hsa 04512, P=1.8e-09). Additionally, multivariate Cox regression confirmed TFF1 as an independent prognostic factor (HR=1.22, 95%CI: 0.082~0.109, P<0.001). The 5-gene model constructed with TFF1 achieved a C-index of 0.71 in the test set. Single-cell transcriptome analysis (n=17) showed that TFF family genes were specifically highly expressed in goblet cells within the tumor microenvironment (log2FC>2, P<0.001) and positively correlated with clinical stage (Spearman ρ=0.68, P=1.3×10⁷). RT-qPCR and WB experiments demonstrated significant differences in the expression of five key adhesion biomarkers (TFF1, TFF2, TFF3, REG4, and SPINK4) in LUAD cell lines (P<0.05).

The 5-gene prognostic model (TFF1/2/3, REG4, SPINK4) constructed through multi-omics data analysis was validated in an independent cohort (AUC=0.77). TFF1 drives tumor progression via goblet cells, offering a novel combination biomarker for liquid biopsy and targeted therapy in LUAD.