The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of the cellular antioxidant response, controlling the expression of genes that counteract oxidative and electrophilic stresses. Many pathological conditions are linked to imbalances in redox homeostasis, illustrating the important role of antioxidant defense systems in preventing the pathogenic effects associated with the accumulation of reactive species. In particular, it is becoming increasingly apparent that the accumulation of lipid peroxides has an important role in driving the pathogenesis of multiple disease states. A key example of this is the recent discovery of a novel form of cell death termed ferroptosis. Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death cascade that has become a key target in the development of anti-cancer therapies, as well as the prevention of neurodegenerative and cardiovascular diseases. In this review, we will provide a brief overview of lipid peroxidation, as well as key components involved in the ferroptotic cascade. We will also highlight the role of the NRF2 signaling pathway in mediating lipid peroxidation and ferroptosis, focusing on established NRF2 target genes that mitigate these pathways, as well as the relevance of the NRF2-lipid peroxidation-ferroptosis axis in disease.

The transcription factor nuclear factor erythroid-2 (NF-E2)-related factor 2 (NRF2) is a central regulator of redox, metabolic, and protein homeostasis that intersects with many other signaling cascades. While the understanding of the complex nature of NRF2 signaling continues to grow, there is only one therapeutic targeting NRF2 for clinical use, dimethyl fumarate, used for the treatment of multiple sclerosis. The discovery of new therapies is confounded by the fact that NRF2 levels vary significantly depending on physiological and pathological context. Thus, properly timed and targeted manipulation of the NRF2 pathway is critical in creating effective therapeutic regimens. In this review, we summarize the regulation and downstream targets of NRF2. Furthermore, we discuss the role of NRF2 in cancer, neurodegeneration, and diabetes, as well as cardiovascular, kidney, and liver disease, with a special emphasis on NRF2-based therapeutics, including those that have made it into clinical trials.

It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy-lysosomal pathway functions to maintain mitochondrial quality, and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function.

NRF2, a transcription factor that has been deemed the master regulator of cellular redox homeostasis, declines with age. NRF2 transcriptionally upregulates genes that combat oxidative stress; therefore, loss of NRF2 allows oxidative stress to go unmitigated and drive the aging phenotype. Oxidative stress is a common theme among the key features associated with the aging process, collectively referred to as the "Hallmarks of Aging", as it disrupts proteostasis, alters genomic stability, and leads to cell death. In this review, we outline the role that oxidative stress and the reduction of NRF2 play in each of the Hallmarks of Aging, including how they contribute to the onset of neurodegenerative disorders, cancer, and other age-related pathologies.

Ferroptosis is a non-apoptotic mode of regulated cell death that is iron and lipid peroxidation dependent. As new mechanistic insight into ferroptotic effectors and how they are regulated in different disease contexts is uncovered, our understanding of the physiological and pathological relevance of this mode of cell death continues to grow. Along these lines, a host of pharmacological modulators of this pathway have been identified, targeting proteins involved in iron homeostasis; the generation and reduction of lipid peroxides; or cystine import and glutathione metabolism. Also, of note, many components of the ferroptosis cascade are target genes of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), indicating its critical role in mediating the ferroptotic response. In this review, we discuss the in vitro, in vivo, and clinical evidence of ferroptosis in disease, including a brief discussion of targeting upstream mediators of this cascade, including NRF2, to treat ferroptosis-driven diseases. Key Mechanisms of the Ferroptotic CascadeAs more and more mechanistic insight into ferroptotic cell death comes to light, three key features continue to be the main Figure 1. NRF2 Regulates Genes Involved in Preventing FerroptosisUnder homeostatic conditions, NRF2 is ubiquitylated and targeted for proteasomal degradation by a KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex. Under conditions of oxidative/electrophilic stress, or as a result of mutations in KEAP1, CUL3, or NRF2 itself, NRF2 is no longer degraded, allowing for nuclear translocation and activation of antioxidant response element (ARE)-containing genes. NRF2 transcriptional targets are involved in mediating iron/metal metabolism, the catabolism/detoxification of reactive intermediates, and glutathione synthesis and metabolism, all of which play a key role in preventing initiation of ferroptosis.