The role of endoplasmic reticulum stress (ERS) in lung cancer remains inadequately explored, with existing studies reporting conflicting results. This study aimed to investigate the causal relationships between ERS-related genes and lung cancer risk.This study used two large-scale genome-wide association studies (GWAS) datasets on lung cancer and integrated multiomics data, including methylation, expression and protein quantitative trait loci, to determine the causal relationships between methylation, gene expression, protein abundance, and lung cancer risk via summary data-based Mendelian randomization (SMR) and colocalization analyses. The findings revealed regulatory effects of methylation on gene and protein expression. Moreover, using cancer databases, key genes and proteins with prognostic significance were validated, and their correlations with immune cell infiltration within the tumor microenvironment were examined.We identified 168 methylation sites associated with lung cancer risk linked to 97 genes. Among these, 20 genes showed altered messenger RNA levels, and 9 had modified protein abundance. Reduced methylation at cg23090046 correlated with increased KLC1 transcription, protein abundance, and lung cancer risk. Similarly, reduced methylation at cg12873919 and cg13989999 was associated with elevated BCL2L1 transcription and heightened lung cancer risk. Patients with high BCL2L1 expression exhibited greater M2 macrophage infiltration, while those with high KLC1 expression exhibited greater B-cell immune suppression, with the high expression of both genes being associated with poor prognosis [KLC1: hazard ratio (HR) =1.29, 95% confident interval (CI): 1.14-1.45; BCL2L1: HR =1.17, 95% CI: 1.01-1.36].This study systematically investigated the causal relationship between ERS-related genes and lung cancer risk, revealing that elevated expression of KLC1 and BCL2L1 may contribute to increased lung cancer risk and be associated with poor prognosis in affected patients.Copyright © 2025 AME Publishing Company. All rights reserved.