Copper-dependent autophagic degradation of GPX4 drives ferroptosis

Autophagy, Journal Year: 2023, Volume and Issue: 19(7), P. 1982 - 1996

Published: Jan. 9, 2023

Ferroptosis is a type of iron-dependent regulated cell death characterized by unrestricted lipid peroxidation and membrane damage. Although GPX4 (glutathione peroxidase 4) plays master role in blocking ferroptosis eliminating phospholipid hydroperoxides, the regulation remains poorly understood. Here, we report an unexpected for copper promoting ferroptotic death, but not cuproptosis, inducing macroautophagic/autophagic degradation GPX4. Copper chelators reduce sensitivity do inhibit other types such as apoptosis, necroptosis, alkaliptosis. Conversely, exogenous increases ubiquitination formation aggregates directly binding to protein cysteines C107 C148. TAX1BP1 (Tax1 1) then acts autophagic receptor subsequent response stress. Consequently, enhances ferroptosis-mediated tumor suppression mouse model pancreatic cancer tumor, whereas attenuate experimental acute pancreatitis associated with ferroptosis. Taken together, these findings provide new insights into link between metal stress autophagy-dependent death.Abbreviations: CALCOCO2, calcium coiled-coil domain 2; GPX4, glutathione 4; MAP1LC3A/B, microtubule 1 light chain 3 alpha/beta; MPO, myeloperoxidase; NCOA4, nuclear coactivator OPTN, optineurin; PDAC, ductal adenocarcinoma; RIPK1, interacting serine/threonine kinase 1; ROS, reactive oxygen species; SLC40A1, solute carrier family 40 member SQSTM1, sequestosome TAX1BP1, Tax1 TEPA, tetraethylenepentamine; TM, tetrathiomolybdate.

Language: Английский

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Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer

Redox Biology, Journal Year: 2022, Volume and Issue: 52, P. 102317 - 102317

Published: April 21, 2022

Chemotherapy is still one of the principal treatments for gastric cancer, but clinical application 5-FU limited by drug resistance. Here, we demonstrate that ferroptosis triggered STAT3 inhibition may provide a novel opportunity to explore new effective therapeutic strategy cancer and chemotherapy We find negative regulation (FNR) signatures are closely correlated with progression chemoresistance cancer. FNR associated genes (GPX4, SLC7A11, FTH1) upregulated in resistant cells xenografts. Further evidence demonstrates binds consensus DNA response elements promoters regulates their expression, thereby establishing STAT3-ferroptosis regulatory axis Genetic activity triggers through lipid peroxidation Fe2+ accumulation cells. further develop potent selective inhibitor, W1131, which significant anti-tumor effects cell xenograft model, organoids patient-derived xenografts (PDX) model partly inducing ferroptosis, thus providing candidate compound advanced Moreover, targeting circuit promotes restores sensitivity chemotherapy. Our finding reveals acts as key regulator multi-pronged mechanism provides

Language: Английский

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Organelle-specific regulation of ferroptosis

Cell Death and Differentiation, Journal Year: 2021, Volume and Issue: 28(10), P. 2843 - 2856

Published: Aug. 31, 2021

Language: Английский

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The interaction between ferroptosis and inflammatory signaling pathways

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(3)

Published: March 21, 2023

Abstract Ferroptosis is an iron-dependent regulated cell death driven by excessive lipid peroxidation. Inflammation one common and effective physiological event that protects against various stimuli to maintain tissue homeostasis. However, the dysregulation of inflammatory responses can cause imbalance immune system, dysfunction death. Recent studies have pointed out activation inflammation, including multiple inflammation-related signaling pathways, lead ferroptosis. Among related signal transduction we focused on five classical namely, JAK-STAT, NF-κB, inflammasome, cGAS-STING MAPK expounded their roles in To date, many agents shown therapeutic effects ferroptosis-related diseases modulating aforementioned pathways vivo vitro. Moreover, regulatory these iron metabolism peroxidation been described detail, contributing further understanding pathophysiological process Taken together, targeting inflammation will provide appropriate ways intervene ferroptosis diseases.

Language: Английский

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NUPR1 is a critical repressor of ferroptosis

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Jan. 28, 2021

Abstract Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Transcription factors play multiple roles in ferroptosis, although the key regulator for ferroptosis iron metabolism remains elusive. Using NanoString technology, we identify NUPR1, stress-inducible transcription factor, as driver resistance. Mechanistically, NUPR1-mediated LCN2 expression blocks ferroptotic death through diminishing accumulation and subsequent oxidative damage. Consequently, depletion mimics NUPR1 deficiency with respect to induction, whereas transfection-enforced re-expression restores resistance NUPR1-deficient cells. Pharmacological or genetic blockade NUPR1-LCN2 pathway (using shRNA, pancreas-specific Lcn2 conditional knockout mice , small molecule ZZW-115) increases activity inducer erastin worsens pancreatitis, suitable mouse models. These findings suggest link between NUPR1-regulated susceptibility.

Language: Английский

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Superoxide Radicals in the Execution of Cell Death

Antioxidants, Journal Year: 2022, Volume and Issue: 11(3), P. 501 - 501

Published: March 4, 2022

Superoxide is a primary oxygen radical that produced when an molecule receives one electron. dismutase (SOD) plays role in the cellular defense against oxidative insult by ROS. However, resulting hydrogen peroxide still reactive and, presence of free ferrous iron, may produce hydroxyl radicals and exacerbate diseases. Polyunsaturated fatty acids are preferred target radicals. Ferroptosis, type necrotic cell death induced lipid peroxides has attracted considerable interest because its pathogenesis many Radical electrons, namely those released from mitochondrial electron transfer complexes, enzymatic reactions, such as lipoxygenases, appear to cause peroxidation. While GPX4 most potent anti-ferroptotic enzyme known reduce alcohols, other antioxidative enzymes also indirectly involved protection ferroptosis. Moreover, several low molecular weight compounds include α-tocopherol, ascorbate, nitric oxide efficiently neutralize thereby suppressing The removal electrons early stages importance protecting ferroptosis diseases related stress.

Language: Английский

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Tumor heterogeneity in autophagy-dependent ferroptosis

Autophagy, Journal Year: 2021, Volume and Issue: 17(11), P. 3361 - 3374

Published: Jan. 6, 2021

Macroautophagy (hereafter referred to as "autophagy") is a lysosome-mediated degradation process that plays complex role in cellular stress, either promoting survival or triggering death. Early studies suggest ferroptosis, an iron-dependent form of regulated cell death, not related autophagy. Conversely, recent evidence indicates the molecular machinery autophagy facilitates ferroptosis through selective anti-ferroptosis regulators. However, mechanism autophagy-dependent remains incompletely understood. Here, we examine early dynamic change protein expression autophagic (e.g., MAP1LC3B and SQSTM1) ferroptotic SLC7A11 GPX4) regulators 60 human cancer lines response two classical activators (erastin RSL3) absence presence lysosomal inhibitor chloroquine. Compared erastin, RSL3 exhibits wider stronger activity upregulation MAP1LC3B-II downregulation SQSTM1 80% (48/60) 63% (38/60) lines, respectively. Both erastin failed affect expression, but they led GPX4 12% (7/60) 3% (2/60) Additionally, intracellular iron exporter SLC40A1/ferroportin-1 was identified new substrate for elimination, its by promoted vitro xenograft tumor mouse models. Together, these findings show heterogeneity which might have different biological behaviors with regard characteristics death.Abbreviations: ATG: Autophagy-related; CQ: Chloroquine; GPX4: Glutathione peroxidase 4; MAP1LC3B/LC3: Microtubule-associated 1 light chain 3 beta: NCOA4: Nuclear Receptor Coactivator ROS: Reactive Oxygen Species; SLC40A1/ferroportin-1: Solute Carrier family 40 Member 1; SLC7A11: Family 7 11; SQSTM1/p62: Sequestosome

Language: Английский

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PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

Cell Reports, Journal Year: 2021, Volume and Issue: 34(8), P. 108767 - 108767

Published: Feb. 1, 2021

Although induction of ferroptosis, an iron-dependent form non-apoptotic cell death, has emerged as anticancer strategy, the metabolic basis ferroptotic death remains poorly elucidated. Here, we show that glucose determines sensitivity human pancreatic ductal carcinoma cells to ferroptosis induced by pharmacologically inhibiting system xc−. Mechanistically, SLC2A1-mediated uptake promotes glycolysis and, thus, facilitates pyruvate oxidation, fuels tricyclic acid cycle, and stimulates fatty synthesis, which finally lipid peroxidation-dependent death. Screening a small interfering RNA (siRNA) library targeting enzymes leads identification dehydrogenase kinase 4 (PDK4) top gene responsible for resistance. PDK4 inhibits blocking dehydrogenase-dependent oxidation. Inhibiting enhances activity xc− inhibitors in vitro suitable preclinical mouse models (e.g., high-fat diet diabetes model). These findings reveal reprogramming potential target overcoming

Language: Английский

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Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 8, 2024

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in biological processes tumors. Intriguingly, mesenchymal dedifferentiated cancer cells, which are usually resistant to apoptosis traditional therapies, exquisitely vulnerable ferroptosis, further underscoring its potential treatment approach for cancers, especially refractory cancers. However, impact ferroptosis on extends beyond direct cytotoxic effect cells. induction not only inhibits but also promotes development due negative anticancer immunity. Thus, comprehensive understanding role crucial successful translation therapy from laboratory clinical applications. In this review, we provide overview recent advancements cancer, covering molecular mechanisms, functions, regulatory pathways, interactions with microenvironment. We summarize applications immunotherapy, radiotherapy, systemic therapy, well inhibition various conditions. finally discuss markers, current challenges future directions cancer.

Language: Английский

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Diversity and complexity of cell death: a historical review

Experimental & Molecular Medicine, Journal Year: 2023, Volume and Issue: 55(8), P. 1573 - 1594

Published: Aug. 23, 2023

Abstract Death is the inevitable fate of all living organisms, whether at individual or cellular level. For a long time, cell death was believed to be an undesirable but unavoidable final outcome nonfunctioning cells, as inflammation inevitably triggered in response damage. However, experimental evidence accumulated over past few decades has revealed different types that are genetically programmed eliminate unnecessary severely damaged cells may damage surrounding tissues. Several death, including apoptosis, necrosis, autophagic and lysosomal which classified pyroptosis, necroptosis, NETosis, inflammatory have been described years. Recently, several novel forms namely, mitoptosis, paraptosis, immunogenic entosis, methuosis, parthanatos, ferroptosis, autosis, alkaliptosis, oxeiptosis, cuproptosis, erebosis, discovered advanced our understanding its complexity. In this review, we provide historical overview discovery characterization highlight their diversity We also briefly discuss regulatory mechanisms underlying each type implications various physiological pathological contexts. This review provides comprehensive can leveraged develop therapeutic strategies for diseases.

Language: Английский

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