<p>The effects of Marein on atherosclerosis progression, particularly its impact on macrophage ferroptosis and the NRF2 pathway, were investigated. RAW264.7 macrophage cells were cultured and treated with oxidized low-density lipoprotein (ox-LDL) to model dysfunction. The effects of Marein were evaluated by treating cells with different concentrations. Ferroptosis inducers and inhibitors were also used to examine the involvement of ferroptosis. Additionally, an NRF2 pathway inhibitor was applied to investigate the underlying mechanisms of action. ApoE^−/− mice fed a high-fat diet were used to induce atherosclerosis. Mice were treated with Marein, and the effects on atherosclerotic plaques, oxidative stress, ferroptosis markers, and the NRF2 pathway were assessed using histological analyses, biochemical assays, and Western blotting. The alleviation of ox-LDL-induced macrophage ferroptosis by Marein was achieved through restoration of GPX4 and xCT expression, reduction of ROS and MDA levels, and restoration of GSH levels. Additionally, Marein activated the NRF2 vias by upregulating nuclear NRF2, NQO1, and HO-1 expression. In ApoE^−/− mice, Marein reduced atherosclerotic plaque formation and lipid deposition, improved lipid metabolism, and attenuated ferroptosis in arterial tissues by activating the NRF2 pathway. Significant therapeutic potential against atherosclerosis was exhibited by Marein through the inhibition of macrophage ferroptosis and activation of the NRF2 pathway.</p> Graphical abstract <p></p>