Bidirectional Mendelian Randomization and Multi-Omics Uncover Causal Serum Metabolites and Neuro-Related Mechanistic Pathways in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a lethal clonal hematopoietic malignancy. Several reports have shown that serum metabolite alterations have been implicated in AML, but the causal relationship and underlying biological mechanisms remain unclear. We performed bidirectional Mendelian randomization (MR) to evaluate the association between 486 serum metabolites and AML. The analytical approaches used to minimize research bias included the inverse variance weighting (IVW), MR-Egger and weighted median (WM) methods. Sensitivity analyses were performed using Cochran's Q Test, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Leave-one-out (LOO) analysis. Metabolic pathway analysis was conducted using the MetaboAnalyst 6.0 platform. We utilized RNA-seq data to explore the potential genes and mechanisms underlying the regulation of AML occurrence by serum metabolites. We identified 23 serum metabolites (13 known and 10 unknown) significantly associated with AML. Sensitivity analyses further validated the robustness of these associations. No evidence of reverse causality was detected by reverse MR analysis. The core pathways were histidine metabolism and fructose/mannose metabolism. Transcriptomic integration revealed 39 overlapping genes (differentially expressed genes vs. metabolite-associated genes) as key mediators, enriched in neuroactive ligand signaling, synaptic vesicle cycle, and GABAergic synapse (KEGG), plus synapse assembly and calmodulin binding and neuron-to-neuron synapse (GO). This study establishes causal links between specific serum metabolites and AML, revealing neuro-related mechanistic pathways. These findings provide novel biomarkers and therapeutic targets for AML precision medicine.