NRF2 is a key regulator of the cellular antioxidant response, controlling genes that counteract oxidative and electrophilic stress. It plays a critical role in preventing lipid peroxidation and ferroptosis, which are iron-dependent, lipid peroxidation-driven cell death processes linked to various diseases. Lipid peroxidation generates reactive lipid species like 4-HNE and MDA, which contribute to disease progression. Ferroptosis is increasingly recognized as a target for cancer therapy and prevention of neurodegenerative and cardiovascular diseases. NRF2 regulates genes involved in iron/metal metabolism, intermediate metabolism, and glutathione synthesis, which are essential for preventing lipid peroxidation and ferroptosis. Key NRF2 target genes include those involved in iron efflux, heme metabolism, and glutathione production. Reactive lipid species can modify NRF2 targets, affecting their function and potentially promoting ferroptosis. In cancer, NRF2 may protect cells from ferroptosis, while in neurodegenerative diseases, its dysfunction could exacerbate lipid peroxidation and ferroptosis. Targeting NRF2 could be a viable strategy for modulating lipid peroxidation and ferroptosis in disease. Inhibitors of NRF2 or its downstream targets may enhance the effectiveness of ferroptosis-inducing agents in cancer therapy. NRF2 activation or inhibition can be used to prevent or treat ferroptosis in various diseases, depending on the context. Understanding the role of NRF2 in lipid peroxidation and ferroptosis is crucial for developing therapeutic strategies.NRF2 is a key regulator of the cellular antioxidant response, controlling genes that counteract oxidative and electrophilic stress. It plays a critical role in preventing lipid peroxidation and ferroptosis, which are iron-dependent, lipid peroxidation-driven cell death processes linked to various diseases. Lipid peroxidation generates reactive lipid species like 4-HNE and MDA, which contribute to disease progression. Ferroptosis is increasingly recognized as a target for cancer therapy and prevention of neurodegenerative and cardiovascular diseases. NRF2 regulates genes involved in iron/metal metabolism, intermediate metabolism, and glutathione synthesis, which are essential for preventing lipid peroxidation and ferroptosis. Key NRF2 target genes include those involved in iron efflux, heme metabolism, and glutathione production. Reactive lipid species can modify NRF2 targets, affecting their function and potentially promoting ferroptosis. In cancer, NRF2 may protect cells from ferroptosis, while in neurodegenerative diseases, its dysfunction could exacerbate lipid peroxidation and ferroptosis. Targeting NRF2 could be a viable strategy for modulating lipid peroxidation and ferroptosis in disease. Inhibitors of NRF2 or its downstream targets may enhance the effectiveness of ferroptosis-inducing agents in cancer therapy. NRF2 activation or inhibition can be used to prevent or treat ferroptosis in various diseases, depending on the context. Understanding the role of NRF2 in lipid peroxidation and ferroptosis is crucial for developing therapeutic strategies.