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Background <p>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.</p> Methods <p>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 <i>FTMT</i>. Cell-type–specific MR was conducted across 14 immune subtypes. Functional enrichment and RT-qPCR of clinical blood samples validated findings.</p> Results <p>Four immune proteins (<i>KIR2DL3</i>, <i>HLA-E</i>, <i>LTA</i>, <i>MICB</i>) were identified as causal risk factors for CeA, acting primarily by downregulating <i>FTMT</i> (all β<sub>1</sub> &lt; 0, <i>P</i> &lt; 0.001). Mediation analysis revealed <i>FTMT</i> explained up to 53% of the immune protein effect. Single-cell MR demonstrated striking cell-type specificity for <i>MICB</i>: higher <i>MICB</i> in NK cells and IgJ<sup>+</sup> B cells was strongly associated with CeA risk (e.g., β = 0.90, <i>P</i> = 4.3 × 10<sup>−6</sup>), while higher <i>MICB</i> in dendritic cells was protective (β = − 0.57, <i>P</i> = 2.1 × 10<sup>−30</sup>). In clinical samples, RT-qPCR confirmed reduced <i>FTMT</i> expression, and plasma ELISA showed elevated circulating <i>LTA</i>, soluble <i>MICB</i>, and soluble <i>HLA-E</i> in CeA patients. Network analysis highlighted NK cell cytotoxicity as a central pathway.</p> Conclusions <p>In summary, our study demonstrates that four immune-related proteins, including <i>MICB</i>, promote cerebral atherosclerosis by downregulating the ferroptosis-protective factor <i>FTMT</i>. Importantly, single-cell MR reveals that <i>MICB</i> 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.</p> Graphical abstract <p></p>

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

  • 期刊论文

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  • 发表日期：

    2026年7月29日

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  • Yonggang Dai,
  • Ye Liu,
  • Yunjun Yan,
  • Haoran Ji,
  • Hongya Wang,
  • Xuewei Zhuang

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Graphical abstract