Poliumoside attenuates endothelial senescence and atherosclerosis by regulating MKRN2-mediated autophagy via the...

Endothelial senescence contributes to the development and progression of atherosclerosis. Poliumoside (Pol), a natural compound with diverse bioactivities, has been shown to attenuate oxidative stress and inflammation, major triggers of senescence. As the role of Pol in Human Umbilical Vein Endothelial Cells (HUVECs) senescence remains elusive, this study aimed to determine whether Pol protects against atherosclerosis by modulating senescence in HUVECs and to elucidate the underlying mechanisms. In the present study, compared with ApoE^-/- control group, Pol reduced senescence marker expression and SA-β-gal-positive area in aortic tissue, and alleviated autophagy dysfunction, thereby attenuating vascular senescence and atherosclerotic lesions. In vitro, Pol suppressed the upregulation of p16, p21, and p53 in senescent HUVECs, decreased Senescence-Associated Secretory Phenotype (SASP) levels, improved autophagy dysfunction, and reduced oxidative stress. Mechanistically, Pol bound to Makorin Ring Finger Protein 2 (MKRN2) and inhibited phosphorylation of the PI3K/AKT/mTOR pathway, mitigating H₂O₂-induced suppression of autophagy and improving cellular senescence. Furthermore, siRNA-mediated downregulation of MKRN2 reversed the effects of Pol on the signaling pathway and autophagy, and attenuated its protective effect against senescence. In summary, Pol attenuates autophagy dysfunction in senescent HUVECs by inhibiting the PI3K/AKT/mTOR pathway via MKRN2, providing a potential therapeutic strategy for cellular senescence and atherosclerosis.