Endoplasmic Reticulum Stress Drives Carotid Atherosclerotic Plaque Instability: Integrative Insights into Biomarkers and Therapeutic Targets
Haifeng Zhou, Zhiwei Zhang, Jianhuang Huang, Zhanghui DingObjective:
Carotid atherosclerosis is a leading cause of stroke, with plaque rupture closely linked to endoplasmic reticulum stress (ERS). However, the precise mechanisms of ERS in plaque instability remain incompletely understood. This study aims to investigate the role of ERS in carotid plaque instability, identify potential biomarkers, and screen candidate therapeutic drugs.
Methods:
Transcriptomic data from the Gene Expression Omnibus (GEO) database (GSE43292 and GSE163154) were analyzed using differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning approaches (Elastic Net, RFE-SVM, GBM) to identify ERS-related differentially expressed genes (ERS-DEGs). The expression, apoptosis, and inflammatory responses of ERS marker genes were validated using qRT-PCR, flow cytometry, and ELISA. CIBERSORT was employed to assess immune cell infiltration, and the Enrichr database was used for drug prediction.
Results:
Four ERS marker genes (TFRC, APOE, NLRP3, NOD2) were identified, showing significantly higher expression in the unstable plaque model (ox-LDL+TNF-α) compared to the stable model (p<0.01), with NLRP3 upregulation being particularly pronounced. Knockdown of these genes significantly reduced apoptosis rates and IL-1β/IL-6 secretion in HUVECs and THP-1-derived macrophages in the unstable model (p<0.01). Immune cell infiltration analysis revealed increased M0 macrophage abundance and decreased CD8+ T cell presence in unstable plaques. Drug prediction identified Bupropion and Triamcinolone as candidate drugs with potential therapeutic value.
Discussion:
ERS drives carotid plaque instability by regulating inflammation and apoptosis. The identified marker genes serve as potential biomarkers, offering novel targets for the diagnosis and treatment of atherosclerosis. The candidate drugs provide directions for future clinical interventions.
Conclusion:
This study suggests that ERS contributes to carotid plaque instability and identifies TFRC, APOE, NLRP3, and NOD2 as genes of interest with potential diagnostic value. Bupropion and triamcinolone emerged as in silico predicted compounds warranting further investigation. These findings provide exploratory insights into ERS in human carotid atherosclerosis and highlight directions for future studies.