Updated project metadata. Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations and even more in women. Since epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions are major alterations found in NSLA, studies have focused on NSLA with EGFR and ALK alteration (EA), but not for NSLA without EGFR and ALK alteration (NENA). To reveal the proteogenomic landscape of NENA, we selected 101 NSLA tissues without EGFR and ALK by targeted sequencing of 1597 FFPE samples, and performed multiomics analyses including whole genome, transcriptome, methylation EPIC array, total proteome, and phosphoproteome. Genome analysis revealed that TP53 (25%), KRAS (22%), ROS1 fusion (13%), SETD2 (11%), and ERRB2 (9%) were the most frequently mutated genes in NENA. Proteogenomic impact analysis found that STK11 and ERBB2 somatic mutations had more profound effects on cancer-associated genes in NENA. From DNA copy number alteration analysis, we identified 22 prognostic proteins whose expression was controlled through transcriptome from copy number alterations Intriguingly, from gene set enrichment analysis, estrogen signaling emerged as the key pathway activated in NENA compared with EA. Evidence from multiomics analysis including copy number gains in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14, also supported the increased estrogen signaling. Finally, the saracatinib, an Src inhibitor, was suggested as a potential drug for targeting activated estrogen signaling in NENA. Taken together, the proteogenomic landscape for NENA from this study will enhance our understanding of the etiology of NSLA.