Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis

International Journal of Molecular Sciences, Год журнала: 2022, Номер 24(1), С. 449 - 449

Опубликована: Дек. 27, 2022

Regulated cell death (RCD) has a significant impact on development, tissue homeostasis, and the occurrence of various diseases. Among different forms RCD, ferroptosis is considered as type reactive oxygen species (ROS)-dependent regulated necrosis. ROS can react with polyunsaturated fatty acids (PUFAs) lipid (L) membrane via formation radical L• induce peroxidation to form L-ROS. Ferroptosis triggered by an imbalance between hydroperoxide (LOOH) detoxification iron-dependent L-ROS accumulation. Intracellular iron accumulation are two central biochemical events leading ferroptosis. Organelles, including mitochondria lysosomes involved in regulation metabolism redox In this review, we will provide overview peroxidation, well key components ferroptotic cascade. The main mechanism that reduces ability glutathione (GSH). GSH, tripeptide includes glutamic acid, cysteine, glycine, acts antioxidant substrate peroxidase 4 (GPX4), which then converted into oxidized (GSSG). Increasing expression GSH inhibit We highlight role xc- GSH-GPX4 pathway regulate system xc-, composed subunit solute carrier family members (SLC7A11 SLC3A2), mediates exchange cystine glutamate across plasma synthesize GSH. Accumulating evidence indicates requires autophagy machinery for its execution. Ferritinophagy used describe removal major storage protein ferritin machinery. Nuclear receptor coactivator (NCOA4) cytosolic bind subsequent degradation ferritinophagy. During ferritinophagy, stored released becomes available biosynthetic pathways. dysfunctional response implicated variety pathological conditions. inducers or inhibitors targeting redox- metabolism-related proteins signal transduction have been developed. simultaneous detection intracellular extracellular markers may help diagnose treat diseases related damage.

Язык: Английский

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Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells

Advanced Science, Год журнала: 2021, Номер 8(22)

Опубликована: Окт. 10, 2021

Abstract Ferroptosis is a new form of regulated cell death, which characterized by the iron‐dependent accumulation lethal lipid peroxides and involved in many critical diseases. Recent reports revealed that cellular energy metabolism activities such as glycolysis, pentose phosphate pathway (PPP), tricarboxylic acid cycle are regulation key ferroptosis markers reduced nicotinamide adenine dinucleotide (NADPH), glutathione (GSH), reactive oxygen species (ROS), therefore imposing potential regulatory roles ferroptosis. Remarkably, tumor cells can activate adaptive metabolic responses to inhibit for self‐preservation upregulation glycolysis PPP. Due rapid proliferation intensified rate, has become target disrupting redox homeostasis induce Based on these emerging insights, impact those‐tumor specific aberrations systematically characterized, rewired glucose compensation through glutamine utilization analyzed underlying molecular mechanisms. Additionally, those ferroptosis‐based therapeutic strategies also discussed exploiting vulnerabilities, may open up avenues treatment clinical context.

Язык: Английский

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Carbon Quantum Dots-Based Nanozyme from Coffee Induces Cancer Cell Ferroptosis to Activate Antitumor Immunity

ACS Nano, Год журнала: 2022, Номер 16(6), С. 9228 - 9239

Опубликована: Май 27, 2022

Carbon quantum dots (CQDs) offer huge potential due to their enzymatic properties as compared natural enzymes. Thus, discovery of CQDs-based nanozymes with low toxicity from resources, especially daily food, implies a promising direction for exploring treatment strategies human diseases. Here, we report biocompatible nanozyme prepared chlorogenic acid (ChA), major bioactive product coffee. We found that ChA CQDs exhibited obvious GSH oxidase-like activities and subsequently promoted cancer cell ferroptosis by perturbation GPX4-catalyzed lipid repair systems. In vivo, dramatically suppressed the tumor growth in HepG2-tumor-bearing mice negligible side toxicity. Particularly, hepatoma H22-bearing mice, recruited massive tumor-infiltrating immune cells including T cells, NK macrophages, thereby converting "cold" "hot" tumors activating systemic antitumor responses. Taken together, our study suggests product-derived coffee can serve biologically safe anticancer therapeutics may aid development nanotechnology-based immunotherapeutic.

Язык: Английский

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The diversified role of mitochondria in ferroptosis in cancer

Cell Death and Disease, Год журнала: 2023, Номер 14(8)

Опубликована: Авг. 14, 2023

Abstract Ferroptosis is a form of regulated cell death induced by iron-dependent lipid peroxidation, and it has been studied extensively since its discovery in 2012. Induced iron overload ROS accumulation, ferroptosis modulated various cellular metabolic signaling pathways. The GSH-GPX4 pathway, the FSP1-CoQ10 GCH1-BH4 DHODH-CoQH2 system sex hormones suppress ferroptosis. Mitochondrial metabolism regulates mitochondria also undergo morphological change during ferroptosis, these changes include increased membrane density reduced mitochondrial cristae. Moreover, energy oxidative phosphorylation ATP production rates lead to decrease glycolysis rate. In addition, excessive stress induces irreversible damage mitochondria, diminishing organelle integrity. production, potential, fusion fission, mitophagy function Notably, some inhibitors target mitochondria. major mechanism for associated with progression cancer. Metastasis-prone or metastatic cancer cells are more susceptible Inducing tumor shows very promising potential treating drug-resistant cancers. this review, we present brief retrospect characteristics then discuss regulation highlight unique role played cells. Furthermore, explain how functions as double-edged sword well novel therapies aimed at selectively manipulating eradication.

Язык: Английский

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Ethyl carbamate triggers ferroptosis in liver through inhibiting GSH synthesis and suppressing Nrf2 activation

Redox Biology, Год журнала: 2022, Номер 53, С. 102349 - 102349

Опубликована: Май 22, 2022

Humans are inevitably exposed to ethyl carbamate (EC) via consumption of fermented food and beverages. EC, known as an environmental toxin, can cause oxidative stress-mediated severe toxicity, but the underlying mechanisms remain unveiled. Ferroptosis is a newly identified ROS-mediated non-apoptotic cell death characterized by iron accumulation excessive lipid oxidation. In this study, we first found that EC triggered ferroptosis in liver cells detection decreased viability, GSH, GPX4 Ferritin levels, well increased MDA contents. inhibitor ferrostatin-1 (Fer-1) pretreatment rescued ferroptotic damage, indicating was critical for EC-caused death. Furthermore, GSH synthesis precursor N-acetylcysteine displayed significant anti-ferroptotic properties suggested depletion might be main under exposure. EC-triggered mainly depended on suppressed inhibition SLC7A11 GCLC expressions. Notably, blocked Nrf2 activation repression phosphorylation modification nuclear translocation, which further resulted occurrence. We also observed EC-induced dysfunction inflammation, accompanied with stress, downregulated signaling Balb/c mice, could effectively reversed Fer-1 tBHQ pretreatment. Together, our study indicated new mechanism attributed inactivation depletion.

Язык: Английский

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Ferroptosis Detection: From Approaches to Applications

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(35)

Опубликована: Фев. 25, 2023

Abstract Understanding the intricate molecular machinery that governs ferroptosis and leveraging this accumulating knowledge could facilitate disease prevention, diagnosis, treatment, prognosis. Emerging approaches for in situ detection of major regulators biological events across cellular, tissue, living subjects provide a multiscale perspective studying ferroptosis. Furthermore, advanced applications integrate latest technologies hold tremendous promise research. In review, we first briefly summarize mechanisms key underlying Ferroptosis are then presented to delineate their design, action, applications. Special interest is placed on multifunctional platforms. Finally, discuss prospects challenges applications, with aim providing roadmap theranostic development broad range ferroptosis‐related diseases.

Язык: Английский

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Heterostructural Nanoadjuvant CuSe/CoSe₂ for Potentiating Ferroptosis and Photoimmunotherapy through Intratumoral Blocked Lactate Efflux

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(13), С. 7205 - 7217

Опубликована: Март 23, 2023

The desirable curative effect in clinical immunotherapy has been challenging due to the immunosuppressive tumor microenvironment (TME) with high lactic acid (LA) metabolism solid tumors. Although targeting metabolic reprogramming of cells can restore survival and function immune TME, it is also plagued by insufficient immunogenicity. Herein, an activatable immunomodulatory nanoadjuvant CuSe/CoSe2@syrosingopine (CSC@Syro) constructed for simultaneously relieving TME boosting response. Specifically, CuSe/CoSe2 (CSC) exhibits TME-activated glutathione (GSH) depletion hydroxyl radical (•OH) generation potential ferroptosis. Meanwhile, remarkable photothermal conversion efficiency elevated photocatalytic ROS level both promote CSC heterostructures induce robust immunogenic cell death (ICD). Besides, loaded syrosingopine inhibitor achieves LA blockade cancer downregulating expression monocarboxylate transporter 4 (MCT4), which could sensitize ferroptosis intracellular milieu acidification neutralize acidic alleviate immunosuppression. Hence, advanced modulation confers potentiated infiltration ICD-stimulated T lymphocytes further reinforces antitumor therapy. In brief, CSC@Syro-mediated synergistic therapy elicit potent immunogenicity suppress proliferation metastasis effectually integrating regulation immunotherapy.

Язык: Английский

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Oxygen Self-Generating Nanoreactor Mediated Ferroptosis Activation and Immunotherapy in Triple-Negative Breast Cancer

ACS Nano, Год журнала: 2023, Номер 17(5), С. 4667 - 4687

Опубликована: Март 2, 2023

The hypoxia microenvironment of solid tumors poses a technological bottleneck for ferroptosis and immunotherapy in clinical oncology. Nanoreactors based on special physiological signals tumor cells are able to avoid various tolerance mechanisms by alleviating the intracellular environment. Herein we reported nanoreactor Cu2-xSe that enabled conversion Cu elements between Cu+ Cu2+ generation O2 consumption GSH content. Furthermore, enhance catalytic ferroptosis-inducing activities nanoreactors, agonist Erastin was loaded ZIF-8 coating surface up-regulate expression NOX4 protein, increase H2O2 content, catalyze produce activate ferroptosis. In addition, nanoreactors were simultaneously functionalized with PEG polymer folic acid molecules, which ensured vivo blood circulation tumor-specific uptake. vitro experiments demonstrated self-supplying can amplify ability generate consume via interconversion Cu2+, impair GPX4/GSH pathway HIF-1α protein expression. At same time, environment, miR301, gene secreted exosomes decreased, ultimately affected phenotype polarization TAMs increased content IFN γ CD8+ T cells, further promoted induced Erastin-loaded nanoreactors. This combined therapeutic strategy activating immune response provides potential application.

Язык: Английский

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Overcoming Hypoxia‐Induced Ferroptosis Resistance via a¹⁹F/¹H‐MRI Traceable Core‐Shell Nanostructure

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(48)

Опубликована: Окт. 12, 2022

Abstract Lipid peroxides accumulation induced ferroptosis is an effective cell death pathway for cancer therapy. However, the hypoxic condition of tumor microenvironment significantly suppresses efficacy ferroptosis. Here, we design a novel nanoplatform to overcome hypoxia‐induced resistance. Specifically, synthesize kind perfluorocarbon (PFOB)@manganese oxide (MnOx) core‐shell nanoparticles (PM‐CS NPs). Owing good carrier O 2 as fuel, PM‐CS NPs can induce higher level ROS generation, lipid peroxidation and GSH depletion, well lower activity GPX4, compared with MnOx alone. Moreover, supplement relieve hypoxia break down storage intracellular droplets increase expression ACSL4 (a symbol sensitivity). Furthermore, upon stimulus or acidity, exhibit “turn on” 19 F‐MRI signal activatable T 1 /T ‐MRI contrast correlating release Mn. Finally, exert high inhibition rate based therapy via synergetic combination ‐mediated enhancement key pathways

Язык: Английский

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The lncRNA BDNF-AS/WDR5/FBXW7 axis mediates ferroptosis in gastric cancer peritoneal metastasis by regulating VDAC3 ubiquitination

International Journal of Biological Sciences, Год журнала: 2022, Номер 18(4), С. 1415 - 1433

Опубликована: Янв. 1, 2022

Ferroptosis is a novel form of cell death that closely associated with the formation many tumors.Our study focused on mechanism by which long noncoding RNAs (lncRNAs) regulate ferroptosis in gastric cancer (GC) peritoneal metastasis (PM).We utilized lncRNA sequencing and protein profiling analysis to identify ferroptosis-associated lncRNAs proteins.qRT-PCR was used analyze expression BDNF-AS FBXW7 GC tissues adjacent normal tissues.Chromatin isolation RNA purification (ChIRP), immunoprecipitation (RIP), chromatin (ChIP), coimmunoprecipitation (co-IP) assays were performed investigate interaction between its downstream targets.Finally, function validated vivo .We demonstrated highly expressed PM tissues.High positively related progression poor prognosis.Functionally, overexpression protected cells from promoted PM.Mechanistically, could recruiting WDR5, thus affecting transcription, regulated VDAC3 through ubiquitination.Conclusively, our research BDNF-AS/WDR5/FBXW7 axis regulates ubiquitination.BDNF-AS might be biomarker for evaluation prognosis treatment GC.

Язык: Английский

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