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Objective <p>Ischemic stroke (IS), a leading cause of global disability and premature mortality, results from cerebral artery occlusion and subsequent ischemic necrosis. Fatty acid metabolism (FAM) plays a crucial role in energy supply and oxidative damage associated with IS, yet reliable biomarkers and targeted therapies remain elusive, necessitating systematic investigation.</p> Methods <p>We integrated peripheral blood transcriptomes (GSE22255 and GSE58294) to identify FAM-related differentially expressed genes (FRDEGs). Consensus clustering of FRDEG expression classified IS subtypes. Weighted gene co-expression network analysis constructed subtype-specific modules. Biomarkers were screened using generalized linear models, least absolute shrinkage and selection operator, support vector machine, and random forest, validated by an independent cohort (GSE16561) and real-time quantitative PCR (RT-qPCR). A diagnostic nomogram was established, and immune infiltration was assessed. Single-cell RNA sequencing (GSE174574) mapped cellular expression, while Connectivity Map analysis and molecular docking predicted potential drugs.</p> Results <p>We identified 14 FRDEGs enriched in the tumor necrosis factor, interleukin-17, and nuclear factor-κB pathways. IS patients were classified into two subtypes. VIM, G0S2, and GPR84 emerged as diagnostic biomarkers, with the nomogram demonstrating high efficacy. RT-qPCR validation confirmed their significant upregulation in the peripheral blood of IS patients. Further analysis showed associations with immune infiltration and distinct single-cell expression patterns. Canertinib and flecainide were identified as high-affinity ligands for GPR84.</p> Conclusion <p>This study highlights the role of FAM in IS, identifies VIM, G0S2, and GPR84 as novel diagnostic biomarkers, and positions GPR84 as a therapeutic target, thereby advancing precision diagnosis and treatment.</p>

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Fatty acid metabolism in ischemic stroke: multi-omics biomarker discovery and therapeutic potential of GPR84

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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  • Jun Wu,
  • Da Wu,
  • Ming Qi,
  • Kuan Jiang

摘要

Objective

Ischemic stroke (IS), a leading cause of global disability and premature mortality, results from cerebral artery occlusion and subsequent ischemic necrosis. Fatty acid metabolism (FAM) plays a crucial role in energy supply and oxidative damage associated with IS, yet reliable biomarkers and targeted therapies remain elusive, necessitating systematic investigation.

Methods

We integrated peripheral blood transcriptomes (GSE22255 and GSE58294) to identify FAM-related differentially expressed genes (FRDEGs). Consensus clustering of FRDEG expression classified IS subtypes. Weighted gene co-expression network analysis constructed subtype-specific modules. Biomarkers were screened using generalized linear models, least absolute shrinkage and selection operator, support vector machine, and random forest, validated by an independent cohort (GSE16561) and real-time quantitative PCR (RT-qPCR). A diagnostic nomogram was established, and immune infiltration was assessed. Single-cell RNA sequencing (GSE174574) mapped cellular expression, while Connectivity Map analysis and molecular docking predicted potential drugs.

Results

We identified 14 FRDEGs enriched in the tumor necrosis factor, interleukin-17, and nuclear factor-κB pathways. IS patients were classified into two subtypes. VIM, G0S2, and GPR84 emerged as diagnostic biomarkers, with the nomogram demonstrating high efficacy. RT-qPCR validation confirmed their significant upregulation in the peripheral blood of IS patients. Further analysis showed associations with immune infiltration and distinct single-cell expression patterns. Canertinib and flecainide were identified as high-affinity ligands for GPR84.

Conclusion

This study highlights the role of FAM in IS, identifies VIM, G0S2, and GPR84 as novel diagnostic biomarkers, and positions GPR84 as a therapeutic target, thereby advancing precision diagnosis and treatment.