The pathogenesis of atherosclerosis is closely related to endothelial cell injury caused by lipid peroxidation-induced ferroptosis. Tanshinone IIA (TSA) protects endothelial tissues from damage. In this study, we investigated whether TSA exerts its protective effect on endothelial cells by inhibiting ferroptosis. Ferroptosis was induced in human coronary artery endothelial cells (HCAECs), and cells were treated with TSA. Morphological examination indicated that TSA exerted a significant protective effect on the HCAECs. This was further confirmed by LDH release and cell death detection assays. Flow cytometry revealed that TSA significantly reduced the excessive accumulation of total cellular ROS and lipid ROS caused by ferroptosis inducers. TSA also restored the reduction of glutathione (GSH), a potent and abundant reductant in cells. In addition, we found that TSA promoted the expression of NRF2, an essential player in response to oxidative stress, and its downstream genes. Immunofluorescent staining revealed that TSA promoted the nuclear translocation of NRF2. Increased nuclear translocation of NRF2 was validated by Western blot evaluation of cytoplasmic and nuclear protein extracts. Furthermore, NRF2 inhibition abolished the protective effects of TSA on HCAECs. These data demonstrate that TSA represses ferroptosis via activation of NRF2 in HCAECs. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).