Tricetin attenuates atherosclerosis by suppressing macrophage ferroptosis via activation of the NRF2 pathway.

Tricetin (TRI) has been reported to have anti-inflammatory and antioxidant effects; however, its therapeutic potential and molecular mechanisms in atherosclerosis remain unclear. In this study, we aimed to investigate the effects of TRI on atherosclerosis. Our findings revealed that TRI inhibits macrophage ferroptosis by activating the NRF2 pathway. In vivo, ApoE mice fed a high-fat diet and injected with TRI showed improved atherosclerosis progression through reduced oxidative stress and suppression of macrophage ferroptosis. In vitro experiments demonstrated that TRI administration increases GPX4 and xCT levels, attenuates oxidative stress, improves mitochondrial function, and inhibits lipid peroxidation, thereby suppressing ox-LDL-induced macrophage ferroptosis. Furthermore, TRI enhanced the nuclear translocation of NRF2. Notably, the protective effects of TRI on antioxidant capacity and ferroptosis were reversed in macrophages treated with ML385 (a specific NRF2 inhibitor). NRF2 knockdown in ApoE mice using AAV-sh-NRF2 significantly reversed TRI-mediated inhibition of atherosclerosis progression and exacerbated macrophage ferroptosis in the plaque. Conclusively, this study identifies TRI as a potential therapeutic agent for atherosclerosis by inhibiting macrophage ferroptosis and oxidative stress through activation of the NRF2 pathway, offering a novel strategy to combat disease progression.