Multi-omics analysis reveals MICB promotes cerebral atherosclerosis through FTMT suppression in NK and plasma cells

Ferroptosis, an iron-dependent form of regulated cell death, is implicated in vascular injury, but how immune-related proteins modulate ferroptosis and cerebral atherosclerosis (CeA) remains unclear.

We performed multi-step Mendelian randomization (MR) integrating plasma proteomics, single-cell eQTL, and FinnGen CeA GWAS data. Mediation MR quantified the role of the ferroptosis regulator FTMT. Cell-type-specific MR was conducted across 14 immune subtypes. Functional enrichment and RT-qPCR of clinical blood samples validated findings.

Four immune proteins (KIR2DL3, HLA-E, LTA, MICB) were identified as causal risk factors for CeA, acting primarily by downregulating FTMT (all β₁ < 0, P < 0.001). Mediation analysis revealed FTMT explained up to 53% of the immune protein effect. Single-cell MR demonstrated striking cell-type specificity for MICB: higher MICB in NK cells and IgJ⁺ B cells was strongly associated with CeA risk (e.g., β = 0.90, P = 4.3 × 10^-6), while higher MICB in dendritic cells was protective (β = - 0.57, P = 2.1 × 10^-30). In clinical samples, RT-qPCR confirmed reduced FTMT expression, and plasma ELISA showed elevated circulating LTA, soluble MICB, and soluble HLA-E in CeA patients. Network analysis highlighted NK cell cytotoxicity as a central pathway.

In summary, our study demonstrates that four immune-related proteins, including MICB, promote cerebral atherosclerosis by downregulating the ferroptosis-protective factor FTMT. Importantly, single-cell MR reveals that MICB acts as a risk factor for CeA specifically in NK cells and plasma cells, providing new mechanistic insight into cell-type-dependent immune regulation of vascular disease.