The global aging crisis has increased the risk of atherosclerosis (AS), positioning vascular senescence as a critical therapeutic target. Procyanidin C1 (PCC1), a bioactive polyphenol from hawthorn, demonstrates dual senolytic and longevity-enhancing effects. This study explored the regulatory role and mechanisms of PCC1 in AS using an ApoEmouse model fed a high-fat diet (HFD) and a D-galactose (D-Gal)-induced cellular senescence model. Hawthorn oligomeric proanthocyanidins (HOPCs), as well as PCC1, showed potent anti-atherosclerotic and anti-aging effects by improving serum lipid metabolism and reducing aortic root plaque, vascular senescence markers and inflammatory adhesion molecules. Metabolomic analysis demonstrated that PCC1 significantly suppresses key enzymes in arachidonic acid (AA) metabolism, thereby decreasing downstream pro-inflammatory mediators. Target identification studies, including drug affinity responsive target stability (DARTS) assay, liquid chromatography-tandem mass spectrometry (LC-MS/MS), cellular thermal shift assay (CETSA), and molecular docking, identified heat shock protein 90 (HSP90) as a direct target of PCC1, leading to inhibition of its downstream signaling. In vitro, PCC1 selectively cleared senescent cells, suppressed the senescence-associated secretory phenotype (SASP), enhanced endothelial nitric oxide synthase (eNOS) phosphorylation, and inhibited the toll-like receptor 2 (TLR2)/nuclear factor kappa-B (NF-κB) pathway, demonstrating multimodal anti-aging and anti-inflammatory effects. Together, these findings indicate that PCC1 mitigates atherosclerosis by targeting both metabolic and inflammatory pathways through senescent cell clearance and HSP90-mediated blockade of the TLR2/NF-κB signaling axis. This dual mechanism highlights PCC1 as a promising vasoprotective agent and supports the potential application of hawthorn extracts in functional foods aimed at preventing aging-related cardiovascular diseases. -/-
