Background:The basement membrane (BM), as a critical component of the extracellular matrix, plays a role in cancer progression. However, the role of the BM in lung adenocarcinoma (LUAD) remains unclear.Methods:A total of 1383 patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts were enrolled in the study, and BM-related differentially expressed genes (BM-DEGs) were screened using weighted gene coexpression network analysis (WGCNA) and differential expression analysis. We next built a prognostic model using Cox regression analysis and separated patients into two groups based on the median risk score. This signature was validated with in vitro experiments, and its mechanism was investigated by enrichment and tumour microenvironment analyses. We also evaluated whether this signature could predict sensitivity to chemotherapy and immunotherapy. Finally, single-cell RNA sequencing analysis was utilized to analyse the expression of signature genes in different cells.Results:Thirsty-seven BM-DEGs were discovered, and a prognostic signature based on 4 BM-DEGs (HMCN2,FBLN5,ADAMTS15andLAD1) was obtained in the TCGA cohort and validated in GEO cohorts. Survival curves and ROC curve analysis demonstrated that the risk score was a significant predictor of survival in all cohorts even when considering the effect of other clinical indexes. Low-risk patients had longer survival times, higher immune cell infiltration levels and better immunotherapeutic responses. Single-cell analysis showed thatFBLN5andLAD1were overexpressed in fibroblasts and cancer cells, respectively, compared to normal cells.Conclusion:This study evaluated the clinical role of the BM in LUAD and primarily explored its mechanism.