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      NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis

      review-article
      a , a , a , b , *
      Redox Biology
      Elsevier

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          Abstract

          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.

          Highlights

          • NRF2 is an important transcriptional regulator of anti-ferroptotic genes.

          • NRF2 target genes prevent lipid peroxidation and the accumulation of free iron.

          • Knockdown of NRF2 is sufficient to sensitize cancer cells to ferroptosis.

          • Pharmacological inhibition of NRF2 can be exploited in combination with ferroptosis inducers.

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          Most cited references41

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          Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

          Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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            ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

            Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
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              Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy

              Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration 1,2 . Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo including organelles, proteins, or intracellular pathogens are targeted for selective autophagy is limited 3 . We employed quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins, including cargo receptors. Like known cargo receptors, NCOA4 was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo-receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species 4 but is degraded via autophagy to release iron 5,6 through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin leads to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy) critical for iron homeostasis and provides a resource for further dissection of autophagosomal cargo-receptor connectivity.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                11 January 2019
                May 2019
                11 January 2019
                : 23
                : 101107
                Affiliations
                [a ]Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA, 85721
                [b ]Arizona Cancer Center, University of Arizona, Tucson, AZ, USA, 85724
                Author notes
                [* ]Corresponding author at: College of Pharmacy, 1703 East Mabel Street, Tucson, AZ 85721, USA. dzhang@ 123456pharmacy.arizona.edu
                Article
                S2213-2317(18)31026-7 101107
                10.1016/j.redox.2019.101107
                6859567
                30692038
                024252a3-ee51-4bce-b2c5-2ab63dc81fa0
                © 2019 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 1 November 2018
                : 13 December 2018
                : 10 January 2019
                Categories
                Implications of lipoxidation in cellular defense and stress pathway

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