Multi-omics analysis reveals MICB promotes cerebral atherosclerosis through FTMT suppression in NK and plasma cells.
6 affiliations
- 1Department of Clinical laboratory, Shandong Provincial Third Hospital, Shandong University, No.11 Middle Wuyingshan Road, Tianqiao District, Jinan, 250031, Shandong, People's Republic of China. [email protected].
- 2School of Nursing and Rehabilitation, Shandong University, Jinan, 250012, Shandong, People's Republic of China.
- 3Jinan Vocational College of nursing, Jinan, 250102, Shandong, People's Republic of China.
- 4Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong China, People's Republic of China.
- 5Department of Clinical laboratory, Shandong Provincial Third Hospital, Shandong University, No.11 Middle Wuyingshan Road, Tianqiao District, Jinan, 250031, Shandong, People's Republic of China.
- 6Department of Clinical laboratory, Shandong Provincial Third Hospital, Shandong University, No.11 Middle Wuyingshan Road, Tianqiao District, Jinan, 250031, Shandong, People's Republic of China. [email protected].
Abstract
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.
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BibTeX
@article{dai2026multiomics,
title = {{Multi-omics analysis reveals MICB promotes cerebral atherosclerosis through FTMT suppression in NK and plasma cells.}},
author = {Yonggang Dai and Ye Liu and Yunjun Yan and Haoran Ji and Hongya Wang and Xuewei Zhuang},
journal = {Clinical epigenetics},
year = {2026},
month = jul,
doi = {10.1186/s13148-026-02212-y},
url = {https://europepmc.org/article/MED/42928267},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Multi-omics analysis reveals MICB promotes cerebral atherosclerosis through FTMT suppression in NK and plasma cells.
AU - Yonggang Dai
AU - Ye Liu
AU - Yunjun Yan
AU - Haoran Ji
AU - Hongya Wang
AU - Xuewei Zhuang
PY - 2026
DA - 2026/07/29
JO - Clinical epigenetics
DO - 10.1186/s13148-026-02212-y
UR - https://europepmc.org/article/MED/42928267
AB - 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.
SN - 1868-7083
ER -