Causal Associations of Cerebrospinal Fluid and Circulating Metabolites With Malignant Brain Neoplasms: A Mendelian Randomization Analysis

BACKGROUND: Emerging insights from immunometabolism underscore the importance of metabolic-immune interactions in shaping the brain tumor microenvironment and potentially influencing brain behavior and neurological outcomes. Although previous studies have suggested potential links between metabolites and risks of malignant brain tumor development, the causal relationship remains unclarified. METHODS: Exposures were extracted from 136,016 Europeans for 233 circulating metabolites and from 689 participants for 338 cerebrospinal fluid (CSF) metabolite levels. Genome-wide association study (GWAS) data for malignant neoplasm of the brain (NCase = 1070, NControl = 345,118) from the FinnGen consortium were used. The primary univariable Mendelian randomization (UVMR) analysis used inverse variance weighting (IVW) and three additional methods for causal assessment. Multivariable MR (MVMR) assessed the direct effects of metabolites, and suggestive biomarkers underwent metabolic pathway enrichment. RESULTS: Twelve metabolic pathways and 21 metabolites (4 circulating biomarkers and 17 CSF metabolites) potentially linked to brain malignancy. The strongest associations were observed for the ratio of omega-3 fatty acids to total fatty acids (IVW: p = 0.01, OR: 0.74, 95% CI: 0.58-0.94) and 5-methylthioadenosine (IVW: p = 0.001, OR: 1.25, 95% CI: 1.09-1.44). Sensitivity analyses confirmed result robustness. MVMR analysis demonstrated direct effects of blood albumin, along with CSF metabolites such as alpha-hydroxyisocaproate, 1-ribosyl-imidazoleacetate, 5-methylthioadenosine, N1-methylinosine, and urate, independent of other factors. CONCLUSIONS: This study reveals metabolite-brain tumor links, shows biomarker potential for screening and prevention, and offers new oncology insights for mechanisms and therapies.