A multilevel genomic approach to uncover causal connections between CPFE and lung cancer subtypes: A two-sample Mendelian randomization study.

Combined pulmonary fibrosis and emphysema (CPFE) and lung cancer cast intertwined shadows, yet the molecular nexus binding them remains largely obscured. By integrating high-resolution transcriptomic landscapes, extensive genome-wide association resources, and a stratified Mendelian randomization (MR) framework, we distilled 809 differentially expressed genes and, in successive steps, confirmed their causal ties to squamous cell carcinoma, adenocarcinoma, and small cell lung cancer. The credibility of these associations was bolstered through 3 sequential validation tiers - eQTL-anchored MR, eQTL-anchored SMR, and pQTL-anchored MR analyses - each reinforcing the robustness of the signals. Within this constellation, CPPED1 emerged as a watchful sentinel that mitigates risk in squamous carcinoma, whereas CD300LF proved a formidable oncogenic catalyst in the small cell lineage. Collectively, these insights illuminate the heritable circuitry linking CPFE and lung cancer, chart avenues for proactive surveillance and precision therapeutics in vulnerable patients, and enrich the conceptual framework of the fibrosis-to-carcinoma transition, inviting deeper multi-omic synthesis and incisive mechanistic exploration.