Genetic-multi-omics causal inference coupled with integrative in-vitro toxicology reveals immune-metabolite mediators for aortic aneurysm risk

Objective Aortic aneurysm (AA) is a life-threatening vascular disease characterized by immune disturbance and metabolic dysregulation. Multi-omics-driven precision toxicity prediction, integrating human genetic causal inference with functional in-vitro toxicology, remains under-explored for uncovering metabolite mediators underlying AA disease risk.This study aimed to dissect metabolite-dependent causal pathways linking immune cells to AA, and evaluate dose-response cytotoxicity of key mediating metabolites toward vascular cells. Methods Two-sample Mendelian randomization (MR) and two-step mediation analysis were performed using European-ancestry GWAS summary datasets covering 731 immune-cell traits, 1,091 plasma metabolites, 3,230 AA cases and 475,964 controls. Complementary in-vitro CCK-8 cytotoxicity experiments on human aortic smooth muscle cells (HASMCs) were further conducted for candidate metabolites Adrenate (22:4n6) and BAFF-R. Results BAFF-R on CD20 − (OR = 0.859, 95%CI: 0.797–0.926, P = 7.17 × 10 −5 ) and, to a lesser extent, Granulocyte AC (OR = 0.900, 95%CI: 0.843–0.961, P = 1.57 × 10 −3 ) emerged as candidate protective immune-cell markers for AA. Adrenate (22:4n6) and Nisinate (24:6n3) mediated 4.47% and 9.84% of these protective effects, respectively. Adrenate triggered significant dose-dependent cytotoxicity in HASMCs. Conclusion This multi-omics genetic-toxicology study provides causal genetic evidence for immune-metabolite regulatory axes in AA pathogenesis. Notably, Adrenate presents dual biological effects: it transmits immune-protective signals but exerts direct vascular cellular toxicity. Our findings highlight the utility of MR-assisted precision toxicity prediction for disease risk evaluation and therapeutic target mining for AA.