Integrative systems biology identifies SIRT1 as a senescence-related theranostic target in atherosclerosis and poliumoside as a natural activator.

Abstract

Cellular senescence contributes to atherosclerotic plaque progression and instability, yet senescence-related diagnostic biomarkers and actionable targets remain incompletely defined. To identify senescence-related diagnostic/therapeutic targets in atherosclerosis using integrative systems biology, and to prioritize natural products that modulate the lead target with experimental validation. Transcriptomic profiles from GSE21545 (126 carotid plaques and 97 paired peripheral blood mononuclear cell samples) were analyzed to identify differentially expressed genes and intersected with CellAge senescence genes. WGCNA and two machine-learning approaches (LASSO and SVM-RFE) were used for feature selection and target prioritization, followed by ROC analysis, functional enrichment, immune infiltration analysis, and PPI network construction. A natural product library (5,565 compounds) was screened against SIRT1 via hierarchical docking, MM-GBSA rescoring, and 100-ns molecular dynamics simulations. Lead compound activity was tested in H 2 O 2 -injured HUVECs using CCK-8 assays, qRT-PCR, Western blotting, and siRNA knockdown. We identified 255 senescence-related differentially expressed genes enriched in oxidative stress and inflammatory pathways. WGCNA and machine learning converged on 10 hub genes, with SIRT1 prioritized based on network centrality and diagnostic performance (AUC = 0.997, 95% CI: 0.992-1.000) and reduced expression in plaque samples. Virtual screening nominated Poliumoside as a high-affinity SIRT1 binder with stable binding dynamics in molecular simulations. In HUVECs, Poliumoside (40 μM) mitigated H 2 O 2 -induced injury and activated the SIRT1/NRF2/HO-1 axis; these effects were attenuated by SIRT1 knockdown. This study highlights SIRT1 as a senescence-related theranostic candidate in atherosclerosis and identifies Poliumoside as a natural SIRT1 activator with endothelial protective activity in vitro .