The article reviews the critical role of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) in mitigating lipid peroxidation and ferroptosis. Lipid peroxidation, driven by reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive lipid species (RLS), is a key factor in various diseases, including cancer, diabetes, neurodegeneration, and cardiovascular disease. Ferroptosis, an iron-dependent, lipid peroxidation-driven form of cell death, has emerged as a promising target for anti-cancer therapies and the prevention of metabolic diseases. NRF2 plays a central role in maintaining redox homeostasis and regulating genes that counteract oxidative stress. The review highlights the involvement of NRF2 in lipid peroxidation and ferroptosis, focusing on established NRF2 target genes that mitigate these pathways. Key components of the ferroptotic cascade, such as glutathione peroxidase 4 (GPX4) and the cystine/glutamate transporter system xC/xCT, are discussed, along with the morphological changes associated with ferroptosis. The article also explores the lipoxidation of NRF2 signaling pathway components, including KEAP1 and downstream targets like PPARγ and AKR1B1, which can be modified by reactive lipids. Finally, the potential of targeting NRF2 to induce ferroptosis as a therapeutic strategy for cancer and other diseases is discussed, emphasizing the importance of understanding the complex interplay between NRF2, lipid peroxidation, and ferroptosis in disease management.The article reviews the critical role of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) in mitigating lipid peroxidation and ferroptosis. Lipid peroxidation, driven by reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive lipid species (RLS), is a key factor in various diseases, including cancer, diabetes, neurodegeneration, and cardiovascular disease. Ferroptosis, an iron-dependent, lipid peroxidation-driven form of cell death, has emerged as a promising target for anti-cancer therapies and the prevention of metabolic diseases. NRF2 plays a central role in maintaining redox homeostasis and regulating genes that counteract oxidative stress. The review highlights the involvement of NRF2 in lipid peroxidation and ferroptosis, focusing on established NRF2 target genes that mitigate these pathways. Key components of the ferroptotic cascade, such as glutathione peroxidase 4 (GPX4) and the cystine/glutamate transporter system xC/xCT, are discussed, along with the morphological changes associated with ferroptosis. The article also explores the lipoxidation of NRF2 signaling pathway components, including KEAP1 and downstream targets like PPARγ and AKR1B1, which can be modified by reactive lipids. Finally, the potential of targeting NRF2 to induce ferroptosis as a therapeutic strategy for cancer and other diseases is discussed, emphasizing the importance of understanding the complex interplay between NRF2, lipid peroxidation, and ferroptosis in disease management.