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Background and objective <p>Vitamin B12 deficiency is an emerging public health concern increasingly linked to neurological disorders, including ischemic stroke, yet its underlying molecular mechanisms remain poorly understood. This study aimed to elucidate the molecular basis of vitamin B12 deficiency-associated ischemic stroke by integrating serum-based metabolomic and proteomic analyses.</p> Methods <p>This study enrolled patients with first-episode acute ischemic stroke, stratified into vitamin B12-deficient (≤ 250 pg/mL) and non-deficient groups, along with age- and sex-matched healthy controls. Serum samples were collected under standardized conditions and analyzed using untargeted metabolomics via ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and data-independent acquisition (DIA)-based quantitative proteomics. Differential metabolites and proteins were identified using variable importance in projection, fold change, and <i>p</i>&#xa0;value thresholds. Integrated multi-omics analysis was conducted using pathway enrichment, correlation matrices, and protein–protein interaction networks to uncover shared mechanisms.</p> Results <p>. Compared to healthy individuals, stroke patients with low vitamin B12 levels exhibited pronounced disruptions in lipid and amino acid metabolism. Proteomic analysis identified several differentially expressed proteins, including matrix metalloproteinase-2 (MMP-2), angiotensinogen (AGT), apolipoprotein B (APOB), and glutathione peroxidase 3 (GPX3), which are involved in inflammation, vascular function, and oxidative stress. Network analysis highlighted gamma-aminobutyric acid (GABA) as a central molecule potentially linking vitamin B12 deficiency with neurovascular injury. Enriched pathways included estrogen signaling, neuroactive ligand-receptor interaction, lipid metabolism and atherosclerosis, and cAMP signaling.</p> Conclusion <p>This study provides the first integrative metabolomic and proteomic evidence that vitamin B12 deficiency may contribute to ischemic stroke by altering lipid metabolism, immune responses, and key regulatory pathways. These findings offer novel molecular insights and potential biomarkers for early detection and targeted intervention in vitamin B12 deficiency-related stroke.</p>

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Integrative proteomic and metabolomic analysis reveals the mechanisms underlying ischemic stroke induced by vitamin B12 deficiency

  • 期刊论文

  • 发表日期：

    2025年10月13日

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  • Li Zhou,
  • Haiyun Wu,
  • Jiani Wang,
  • Yilin Wang,
  • Yanli Cai,
  • Yong Zhao,
  • Yu Ren,
  • Qin Yang

摘要

Background and objective

Vitamin B12 deficiency is an emerging public health concern increasingly linked to neurological disorders, including ischemic stroke, yet its underlying molecular mechanisms remain poorly understood. This study aimed to elucidate the molecular basis of vitamin B12 deficiency-associated ischemic stroke by integrating serum-based metabolomic and proteomic analyses.

Methods

This study enrolled patients with first-episode acute ischemic stroke, stratified into vitamin B12-deficient (≤ 250 pg/mL) and non-deficient groups, along with age- and sex-matched healthy controls. Serum samples were collected under standardized conditions and analyzed using untargeted metabolomics via ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and data-independent acquisition (DIA)-based quantitative proteomics. Differential metabolites and proteins were identified using variable importance in projection, fold change, and p value thresholds. Integrated multi-omics analysis was conducted using pathway enrichment, correlation matrices, and protein–protein interaction networks to uncover shared mechanisms.

Results

. Compared to healthy individuals, stroke patients with low vitamin B12 levels exhibited pronounced disruptions in lipid and amino acid metabolism. Proteomic analysis identified several differentially expressed proteins, including matrix metalloproteinase-2 (MMP-2), angiotensinogen (AGT), apolipoprotein B (APOB), and glutathione peroxidase 3 (GPX3), which are involved in inflammation, vascular function, and oxidative stress. Network analysis highlighted gamma-aminobutyric acid (GABA) as a central molecule potentially linking vitamin B12 deficiency with neurovascular injury. Enriched pathways included estrogen signaling, neuroactive ligand-receptor interaction, lipid metabolism and atherosclerosis, and cAMP signaling.

Conclusion

This study provides the first integrative metabolomic and proteomic evidence that vitamin B12 deficiency may contribute to ischemic stroke by altering lipid metabolism, immune responses, and key regulatory pathways. These findings offer novel molecular insights and potential biomarkers for early detection and targeted intervention in vitamin B12 deficiency-related stroke.