Quercetin alleviates postmenopausal atherosclerosis by suppressing endothelial cell ferroptosis via regulating the KEAP1/NRF2/GPX4 signalling pathway

Background and Purpose Postmenopausal women experience accelerated progression of atherosclerosis, yet the underlying mechanisms remain poorly understood and effective therapeutic strategies are limited. This study aimed to investigate the protective effects of quercetin (QCT) against postmenopausal atherosclerosis and to elucidate its mechanism through the KEAP1/NRF2 pathway‐mediated inhibition of endothelial cell ferroptosis. Experimental Approach A postmenopausal atherosclerosis model was established using bilateral ovariectomy (OVX) combined with a high‐fat diet in ApoE −/− female mice. The therapeutic effects of QCT and a ferroptosis inhibitor Fer‐1 were evaluated through histological, biochemical and molecular analyses. For in vitro studies, ox‐LDL‐induced endothelial cells were conducted to examine the antiferroptosis mechanism of QCT. The role of NRF2 was further validated using AAV‐shNRF2 in vivo and ML385 (NRF2 inhibitor) in vitro. Key Results Both QCT and Fer‐1 significantly attenuated postmenopausal atherosclerosis progression, as evidenced by reduced lipid peroxidation, decreased iron deposition and suppressed endothelial cell ferroptosis in OVX mice. QCT treatment up‐regulated GPX4 whilst down‐regulating ACSL4 expression and reducing ROS accumulation in ox‐LDL‐induced endothelial cells. Mechanistically, QCT promoted KEAP1 ubiquitination and subsequent degradation, leading to NRF2 nuclear translocation and activation of downstream antioxidant pathways. The protective effects of QCT were significantly diminished by NRF2 inhibition, both in vitro and in vivo. Conclusion and Implications This study demonstrates that QCT alleviated postmenopausal atherosclerosis by inhibiting endothelial cell ferroptosis through KEAP1 ubiquitination‐mediated activation of the NRF2/GPX4 pathway. These findings provide novel insights into the molecular mechanisms of postmenopausal atherosclerosis and suggest QCT as a potential therapeutic agent for this condition.