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已发表论文
金属蛋白酶-9 作为焦亡-缺氧协同效应器驱动缺血性脑卒中的免疫重塑：一种经多组学验证的诊断生物标志物和治疗靶点
Authors Wu J , Wu D, Qi M, Jiang K
Received 27 June 2025
Accepted for publication 26 October 2025
Published 6 November 2025 Volume 2025:18 Pages 6723—6740
DOI https://doi.org/10.2147/IJGM.S550007
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Woon-Man Kung
Jun Wu,* Da Wu,* Ming Qi, Kuan Jiang
Department of Neurosurgery, Yixing People’s Hospital, Yixing, Jiangsu, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Kuan Jiang, Department of Neurosurgery, Yixing People’s Hospital, Yixing, Jiangsu, People’s Republic of China, Email staff1671@yxph.com
Purpose: As a predominant contributor to disability and premature mortality worldwide, ischemic stroke (IS) urgently requires breakthroughs in early diagnostic biomarkers. The synergistic regulatory roles of pyroptosis and hypoxia, two critical pathological mechanisms in IS, require systematic exploration.
Patients and Methods: We integrated two IS peripheral blood transcriptomic datasets (GSE66724 and GSE58294) to identify differentially expressed genes (DEGs) linked to pyroptosis and hypoxia. Co-expression networks were constructed using weighted gene co-expression network analysis. Diagnostic biomarkers were identified through the Least Absolute Shrinkage and Selection Operator, Support Vector Machine, and Random Forest algorithms, with validation performed in an independent cohort (GSE16561) and real-time quantitative PCR (RT-qPCR). Single-cell sequencing (GSE174574) was used to map cellular expression patterns of diagnostic genes. Candidate drugs were identified through the Connectivity Map (CMAP) database, with molecular docking validating their target protein interactions.
Results: We identified 32 pyroptosis-related and 50 hypoxia-related DEGs, with enrichment analyses indicating their involvement in inflammatory responses, NF-κB signaling, and tumor necrosis factor pathways. Cross-algorithm validation identified matrix metalloproteinase-9 (MMP9) as a diagnostic biomarker. RT-qPCR revealed significantly elevated MMP9 levels in the peripheral blood of IS patients (p < 0.01). Immune microenvironment profiling showed positive correlations between MMP9 expression and macrophage/neutrophil infiltration. Single-cell sequencing confirmed predominant MMP9 expression in granulocytes. Drug prediction via CMAP and molecular docking identified Benperidol and Fluspirilene as high-affinity ligands for MMP9.
Conclusion: This study employed multi-omics analysis followed by experimental validation to provide robust and systematic evidence supporting the diagnostic value and therapeutic potential of MMP9 in IS.
Keywords: hypoxia, ischemic stroke, molecular docking, pyroptosis, single-cell
Department of Neurosurgery, Yixing People’s Hospital, Yixing, Jiangsu, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Kuan Jiang, Department of Neurosurgery, Yixing People’s Hospital, Yixing, Jiangsu, People’s Republic of China, Email staff1671@yxph.com
Purpose: As a predominant contributor to disability and premature mortality worldwide, ischemic stroke (IS) urgently requires breakthroughs in early diagnostic biomarkers. The synergistic regulatory roles of pyroptosis and hypoxia, two critical pathological mechanisms in IS, require systematic exploration.
Patients and Methods: We integrated two IS peripheral blood transcriptomic datasets (GSE66724 and GSE58294) to identify differentially expressed genes (DEGs) linked to pyroptosis and hypoxia. Co-expression networks were constructed using weighted gene co-expression network analysis. Diagnostic biomarkers were identified through the Least Absolute Shrinkage and Selection Operator, Support Vector Machine, and Random Forest algorithms, with validation performed in an independent cohort (GSE16561) and real-time quantitative PCR (RT-qPCR). Single-cell sequencing (GSE174574) was used to map cellular expression patterns of diagnostic genes. Candidate drugs were identified through the Connectivity Map (CMAP) database, with molecular docking validating their target protein interactions.
Results: We identified 32 pyroptosis-related and 50 hypoxia-related DEGs, with enrichment analyses indicating their involvement in inflammatory responses, NF-κB signaling, and tumor necrosis factor pathways. Cross-algorithm validation identified matrix metalloproteinase-9 (MMP9) as a diagnostic biomarker. RT-qPCR revealed significantly elevated MMP9 levels in the peripheral blood of IS patients (p < 0.01). Immune microenvironment profiling showed positive correlations between MMP9 expression and macrophage/neutrophil infiltration. Single-cell sequencing confirmed predominant MMP9 expression in granulocytes. Drug prediction via CMAP and molecular docking identified Benperidol and Fluspirilene as high-affinity ligands for MMP9.
Conclusion: This study employed multi-omics analysis followed by experimental validation to provide robust and systematic evidence supporting the diagnostic value and therapeutic potential of MMP9 in IS.
Keywords: hypoxia, ischemic stroke, molecular docking, pyroptosis, single-cell