Abstract
BACKGROUND: The mechanisms by which various circulating metabolites influence bladder cancer (BLCA) progression via differentially expressed metabolic pathway genes remain unclear. METHODS: This study employed a bidirectional two-sample Mendelian randomization (MR) method to investigate potential causal relationships between circulating metabolites and the risk of BLCA. Thorough methodological assessments were conducted alongside extensive sensitivity analyses to guarantee robustness. The subsequent KEGG pathway enrichment analysis identified biologically significant metabolic pathways, which were subsequently cross-referenced with differentially expressed gene-associated metabolic pathways from TCGA and GEO datasets. Ultimately, we developed graphic representations of the interconnections between metabolic and genetic pathways. RESULTS: Our study identified 27 circulating metabolites with causal associations to BLCA, comprising 18 risk variables and 9 protective factors. Sensitivity analyses were conducted to validate the robustness of the results. Reverse Mendelian Randomization analysis eliminated metabolite-level influences from bladder cancer. Pathway enrichment analysis of these metabolites revealed 41 pathways, with 3 consistently modified in TCGA and GEO datasets. The visualizations of the pathways clarified potential mechanistic connections between metabolic dysregulation and chromosomal changes in the pathogenesis of BLCA. CONCLUSION: This work explored causal links between specific circulating metabolites and BLCA, uncovering functionally significant metabolic pathways through combined metabolomic and Transcriptomic studies. The identified correlations between metabolites and genes provided a new understanding of BLCA metabolomics and laid the groundwork for the development of tailored metabolic treatments.