Genetically supported mediators linking peripheral metabolism to cerebral ischemia: a multi-omics characterization of HMGCR, TLR4, and MMP9 in angina pectoris and stroke.

Emerging evidence implicates peripheral metabolic disturbances in the pathogenesis of cerebrovascular diseases. However, the specific molecular conduits linking angina pectoris (AP) to ischemic stroke (IS) remain elusive. To address this, we evaluated the causal effect of AP on IS subtypes utilizing Bayesian-weighted Mendelian randomization (BWMR) based on large-scale GWAS meta-data (n = 628 000). Cross-tissue transcriptomic analyses, coupled with the Boruta feature selection algorithm, were employed to screen for candidate mediators, with subsequent validation of genetic causality and therapeutic viability via standard Mendelian randomization (MR), colocalization analysis, and molecular docking. Furthermore, their involvement in cellular immunity was characterized using CIBERSORT and single-cell ribonucleic acid-seq (scRNA-seq). BWMR established a robust causal relationship from stable AP to IS (OR = 1.13, P = .004). Multi-omics integration identified 18 hub macromolecules, prioritizing HMGCR, TLR4, and MMP9 as the primary candidate mediators enriched in lipid metabolism and inflammatory pathways. MR corroborated the genetic relevance of these loci to IS risk, while molecular docking confirmed their structural druggability. A multilayer perceptron classifier (MLPC) utilizing these targets demonstrated high predictive accuracy for IS (AUC = 0.82-0.90). Crucially, scRNA-seq revealed that TLR4 and MMP9 expression in peripheral immune cells (CD8+ T cells and neutrophils) may drive a metabolic-inflammatory cascade, functioning as vital conduits for peripheral-to-brain signal transduction. In conclusion, this multi-omics framework identifies HMGCR, TLR4, and MMP9 as genetically supported mediators bridging AP and IS, elucidating peripheral-cerebral crosstalk and highlighting actionable targets for clinical risk stratification and pharmacological repurposing.