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<p>Growing evidence implicates solute carrier (SLC) superfamily in atherosclerosis (AS) pathogenesis. This study identified SLC22A3 as a novel AS biomarker and therapeutic target using multi-omics analysis. Integrating WGCNA and machine learning (LASSO, SVM-RFE, XGBoost, Random Forest) on bulk RNA-seq (GSE43292) pinpointed SLC22A3. External datasets (GSE28829, GSE163154) confirmed significant SLC22A3 downregulation in AS (<i>P</i> &lt; 0.001) and high diagnostic accuracy (AUC &gt; 0.9). SMR analysis revealed a causal genetic link between SLC22A3 expression and reduced AS risk (<i>P</i> &lt; 0.05, OR = 0.512 (95% CI: 0.280–0.939))). scRNA-seq showed SLC22A3 specifically expressed in smooth muscle cells (SMCs), significantly reduced in symptomatic patients. Molecular docking and molecular dynamics simulation nominated six FDA-approved drugs as potential SLC22A3-targeting therapeutics. Experimental validation further confirmed the significant downregulation of SLC22A3 at both mRNA and protein levels. SLC22A3 is a promising diagnostic biomarker and therapeutic target for AS, functionally linked to SMCs.</p> Graphical Abstract <p></p>

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Comprehensive Analysis of Bulk RNA-seq, Machine Learning, Mendelian Randomization, and Single-Cell Sequencing Unravels SLC22A3 as a Solute Carrier Superfamily-Associated Biomarker in Atherosclerosis

  • 期刊论文

  • 发表日期：

    2026年3月10日

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  • Yongchao Yu,
  • Lan Wang,
  • Tianhui Wang,
  • Ya Zhang,
  • Xiaomeng Su,
  • Xingyang Dai,
  • Xiangang Mo

摘要

Growing evidence implicates solute carrier (SLC) superfamily in atherosclerosis (AS) pathogenesis. This study identified SLC22A3 as a novel AS biomarker and therapeutic target using multi-omics analysis. Integrating WGCNA and machine learning (LASSO, SVM-RFE, XGBoost, Random Forest) on bulk RNA-seq (GSE43292) pinpointed SLC22A3. External datasets (GSE28829, GSE163154) confirmed significant SLC22A3 downregulation in AS (P < 0.001) and high diagnostic accuracy (AUC > 0.9). SMR analysis revealed a causal genetic link between SLC22A3 expression and reduced AS risk (P < 0.05, OR = 0.512 (95% CI: 0.280–0.939))). scRNA-seq showed SLC22A3 specifically expressed in smooth muscle cells (SMCs), significantly reduced in symptomatic patients. Molecular docking and molecular dynamics simulation nominated six FDA-approved drugs as potential SLC22A3-targeting therapeutics. Experimental validation further confirmed the significant downregulation of SLC22A3 at both mRNA and protein levels. SLC22A3 is a promising diagnostic biomarker and therapeutic target for AS, functionally linked to SMCs.

Graphical Abstract