This study investigated whether quercetin protects endothelial cells from Oxidized Low-Density Lipoprotein (Ox-LDL)-induced injury by inhibiting ferroptosis via the sirtuin 3 (SIRT3)/AMP-activated protein kinase (AMPK) signaling pathway. Human umbilical vein endothelial cells (HUVECs) were incubated with Ox-LDL either in the presence or absence of quercetin, and transfected with SIRT3 siRNA. Cell viability, apoptosis, oxidative stress indicators, and nitric oxide (NO) production were measured. Ferroptosis-related proteins and signaling pathway proteins were analyzed by Western blot. Quercetin improved cell viability, reduced apoptosis, and attenuated oxidative injury as well as ferroptosis among Ox-LDL-stimulated HUVECs. Mechanistically, quercetin upregulated the ferroptosis-protective factors glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) while downregulating the pro-ferroptotic enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4), thereby restoring antioxidant capacity and resistance to ferroptosis. In addition, quercetin markedly increased SIRT3 expression and AMPK phosphorylation, whereas SIRT3 silencing significantly attenuated both the molecular alterations and the associated functional improvements. Quercetin protected endothelial cells against Ox-LDL-provoked injury via suppressing ferroptosis through SIRT3/AMPK pathway activation. These findings identify a previously unrecognized SIRT3/AMPK-dependent mechanism underlying quercetin-mediated endothelial protection and provide mechanistic insight relevant to atherosclerosis.
Gao et al. (2026) studied this question.