Abstract
This study seeks to understand the causal association between serum metabolites and different lung cancer types, an area yet to be extensively studied. We Used a two-sample Mendelian randomization (TSMR) approach, utilizing 486 blood metabolites as exposures and 3 distinct lung cancer types genome-wide association studies datasets as outcomes. We employed inverse variance weighting, MR-Egger, weighted median, simple mode, and weighted mode to estimate causal effects. We performed sensitivity analyses using Cochran Q test, MR-Egger intercept test, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Linkage disequilibrium score (LDSC) analysis was conducted on the selected metabolites, and common confounding single nucleotide polymorphisms were eliminated using the human genotype-phenotype association Database. Metabolic pathway analysis was performed with MetaboAnalyst 5.0 software. Subsequently, a multivariate Mendelian randomization analysis was conducted to ascertain independent risk exposures. Our findings suggest independent risk factors for specific types of lung cancer: 7-methylxanthine and isoleucine for lung adenocarcinoma, cysteine and 1-arachidonoylglycerophosphocholine are identified as independent protective and risk factors for squamous lung cancer. Undecanoate (11:0) with Linoleate (18:2n6) showed a protective effect for small cell lung cancer. Additionally, 11 metabolic pathways were associated with lung cancer. This novel perspective offers a multidimensional understanding of lung cancer phenotypes, providing valuable guidance for identifying and screening of diverse lung cancer phenotypes.