Circulating proteins associated with histological subtypes of lung cancer from genetic and population-based perspectives

Lung cancer (LC) is the leading cause of cancer-related mortality worldwide, accounting for millions of deaths annually. Its major subtypes—lung squamous carcinoma (LUSC), lung adenocarcinoma, and small-cell LC—exhibit distinct risk factors and genetic susceptibilities, necessitating the use of subtype-specific biomarkers. Two-sample Mendelian randomization (MR) analyses were conducted using protein quantitative trait loci from the UK Biobank Pharma Proteomics Project and deCODE datasets. A robust analytical framework, including reverse MR, meta-analysis, summary-data-based MR tests, and colocalization, cisMR-cML, MR.CUE and phenotype scanning analyses were used to identify proteins associated with LC risk. We conducted a systematic review to contextualize our research findings. Follow-up analyses, including pathway enrichment, protein-protein interaction network analysis, and druggability evaluations, were used to explore the mechanisms and therapeutic potential of the identified proteins. Significant proteins were validated using population-level proteomic data from the UK Biobank (UKB). The results showed that twenty-five proteins were significantly associated with LC or its subtypes, including 15 novel findings. 60S ribosomal protein L14 (RPL14) and advanced glycosylation end-product-specific receptor (AGER) emerged as the strongest discovery, demonstrating consistent and significant associations across both MR and population-level analyses. RPL14 exhibited positive associations with overall LC risk (MR_meta: odds ratio [OR]: 2.012, 95% confidence interval [CI]: 1.297–3.119; UKB: OR: 1.509, 95% CI: 1.015–2.244). Similarly, AGER showed significant protective effects against LUSC risk (MR_meta: OR: 0.572, 95%CI: 0.368–0.889; UKB: OR: 0.366, 95% CI: 0.158–0.850). Pathway analysis revealed the involvement of these proteins in immune regulation and tumorigenesis. Among the 13 identified druggable targets, RPL14 and AGER showed therapeutic potential as approved or investigational drugs targeting these proteins. These findings offer new insights into the pathogenesis of LC and potential therapeutic targets.