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<p>Atherosclerosis (AS) is driven by intertwined inflammatory responses and vascular wall remodeling, yet the core regulatory networks and actionable targets underlying plaque formation remain incompletely defined. Bulk transcriptomic data from GSE43292, comprising paired advanced carotid plaques and distant early-stage lesion tissues from 32 patients, were analyzed to identify differentially expressed genes (DEGs), followed by WGCNA and intersection with GeneCards-derived AS-related genes. Candidate genes were mapped to a STRING PPI network, and hub genes were prioritized using four Cytoscape algorithms (MCC, EPC, Stress, Degree). Functional annotation (GO/KEGG), immune infiltration, and single-gene GSEA were performed. A 10 × scRNA-seq dataset (GSE159677) was used for cell-type annotation, compositional comparison, cell–cell communication, and hub-gene localization. Drug prediction was conducted, followed by molecular docking of candidate compounds with hub proteins. Finally, an oxLDL-induced in vitro model was used for validation by CCK-8, ROS staining, Western blotting, and qRT-PCR. Seven hub genes (SMAD4, CASP8, PARP1, CRKL, CDK6, VDAC1, KHDRBS1) were identified. Enrichment analyses linked these hubs to cell death/stress regulation, immune-related programs, and vascular remodeling. Immune infiltration suggested marked immune reconfiguration in plaques. Single-gene GSEA highlighted coordinated remodeling of vascular smooth muscle contraction, gap junction signaling, and lipid/NAD-associated metabolism. scRNA-seq analysis indicated joint contributions from myeloid and vascular structural cells, with hub genes showing cell-type–biased enrichment. Quercetin emerged as a candidate compound; docking supported favorable multi-target binding (strongest for PARP1 and CDK6). Experimentally, oxLDL upregulated hub-gene mRNA/protein levels, while quercetin significantly attenuated these increases. We define an AS-associated hub-gene network with single-cell context and provide convergent computational and experimental evidence that quercetin exerts endothelial-protective effects consistent with multi-target modulation of the hub-gene network, supporting its therapeutic potential in AS.</p>

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Multi-layer network biology combined with single-cell evidence reveals core regulatory nodes in atherosclerotic plaques and potential drug-targeting directions

  • 期刊论文

  • 发表日期：

    2026年7月7日

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  • Dajun Huang,
  • Ying Liu,
  • Yilan Wang,
  • Jinming Hu,
  • Hanzhang Tang,
  • Yongjun Yin,
  • Lingqiu Kong

摘要

Atherosclerosis (AS) is driven by intertwined inflammatory responses and vascular wall remodeling, yet the core regulatory networks and actionable targets underlying plaque formation remain incompletely defined. Bulk transcriptomic data from GSE43292, comprising paired advanced carotid plaques and distant early-stage lesion tissues from 32 patients, were analyzed to identify differentially expressed genes (DEGs), followed by WGCNA and intersection with GeneCards-derived AS-related genes. Candidate genes were mapped to a STRING PPI network, and hub genes were prioritized using four Cytoscape algorithms (MCC, EPC, Stress, Degree). Functional annotation (GO/KEGG), immune infiltration, and single-gene GSEA were performed. A 10 × scRNA-seq dataset (GSE159677) was used for cell-type annotation, compositional comparison, cell–cell communication, and hub-gene localization. Drug prediction was conducted, followed by molecular docking of candidate compounds with hub proteins. Finally, an oxLDL-induced in vitro model was used for validation by CCK-8, ROS staining, Western blotting, and qRT-PCR. Seven hub genes (SMAD4, CASP8, PARP1, CRKL, CDK6, VDAC1, KHDRBS1) were identified. Enrichment analyses linked these hubs to cell death/stress regulation, immune-related programs, and vascular remodeling. Immune infiltration suggested marked immune reconfiguration in plaques. Single-gene GSEA highlighted coordinated remodeling of vascular smooth muscle contraction, gap junction signaling, and lipid/NAD-associated metabolism. scRNA-seq analysis indicated joint contributions from myeloid and vascular structural cells, with hub genes showing cell-type–biased enrichment. Quercetin emerged as a candidate compound; docking supported favorable multi-target binding (strongest for PARP1 and CDK6). Experimentally, oxLDL upregulated hub-gene mRNA/protein levels, while quercetin significantly attenuated these increases. We define an AS-associated hub-gene network with single-cell context and provide convergent computational and experimental evidence that quercetin exerts endothelial-protective effects consistent with multi-target modulation of the hub-gene network, supporting its therapeutic potential in AS.