Association between lipid metabolism and lung adenocarcinoma: Evidence from Mendelian randomization and tissue microbiome analysis

Background: Tissue-resident microbiota play an important role in lung cancer development. This study aimed to characterize the microbiota profile associated with fatty acid metabolism and related genes and examine its effect on treatment outcomes in lung cancer. Methods: Genome-wide association data on saturated fatty acid ratio, total cholesterol, and linoleic acid ratio were analyzed with lung adenocarcinoma as the outcome. Mendelian randomization (MR) and multivariable MR using significant single nucleotide polymorphisms assessed causal effects with sensitivity analyses. TCGA and GEO microbial data were explored via GSEA, STRING, and CIBERSORT, and Bacillus velezensis was validated in tumor tissue by quantitative polymerase chain reaction. Results: MR identified saturated fatty acids and total cholesterol as risk factors for lung adenocarcinoma (LUAD), while linoleic acid was protective. Microbial profiling showed distinct tumor versus adjacent tissue communities, with Bacillus velezensis enriched in LUAD. Its abundance was negatively associated with the cholesterol-response pathway (GOBP_CELLULAR_RESPONSE_TO_CHOLESTEROL). Twelve cholesterol-related genes were differentially expressed, and a derived risk model predicted poor prognosis. Among them, GPLD1 exhibited tumor-suppressor characteristics, with lower tumor expression linked to worse survival. GPLD1 is detectable in plasma (~2.8 mg/L) and reduced in lung cancer patients, supporting its potential as a noninvasive biomarker. Conclusion: Our findings suggest a causal link between the components of a high-fat diet and LUAD by identifying key genes and microbial communities. Moreover, GPLD1 represents a promising biomarker for the early diagnosis and prognosis of this patient population.