Molecular stratification of endoplasmic reticulum stress identifies DKK1 as a key ERS-associated regulator in lung adenocarcinoma

Background Persistent endoplasmic reticulum stress (ERS) contributes to lung adenocarcinoma (LUAD) progression, but interpretable ERS-based stratification systems and functionally relevant regulators linking ERS adaptation to ER-phagy remain insufficiently defined. Results We constructed 12 functionally defined ERS-related gene sets and applied ssGSEA to 504 TCGA-LUAD samples, identifying high, moderate, and low ERS subtypes. The high-ERS subtype was associated with advanced T stage, poorer overall survival, enhanced proliferation/cell-cycle activity, metabolic activation, and increased invasion-related activity. Differential expression, survival, and LASSO-Cox analyses identified DKK1, FAM83A, and UCK2 as ERS-associated prognostic genes. A three-gene risk score showed consistent prognostic performance in TCGA and independent GEO cohorts, and its integration with T stage yielded a prognostic nomogram in the TCGA cohort. Single-cell transcriptomics showed tumor-cell-biased enrichment of these genes and the derived signature score, with DKK1 displaying the most prominent malignant epithelial expression pattern. Tissue microarray analysis confirmed that high DKK1 expression was associated with poor prognosis. In A549 and NCI-H1395 cells, knockdown of DKK1 or CKAP4 reduced RETREG1 expression, whereas recombinant DKK1 restored RETREG1 levels after DKK1 knockdown alone but not after combined DKK1 and CKAP4 knockdown. Functional assays showed that DKK1 promoted proliferation, clonogenicity, migration, and invasion while suppressing apoptosis. Stable DKK1 knockdown also inhibited xenograft tumor growth and reduced RETREG1 expression in vivo. Conclusions This study establishes an interpretable ERS-based molecular stratification framework for LUAD and identifies DKK1, FAM83A, and UCK2 as tumor-cell-biased ERS-associated prognostic markers. Our experimental findings support a DKK1–CKAP4–RETREG1 regulatory axis and suggest that this axis may contribute to ER-phagy-related ERS adaptation and malignant progression in LUAD, highlighting DKK1 as a potential biomarker and therapeutic target.