Targeting ferroptosis as a vulnerability in cancer

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 22(7), P. 381 - 396

Published: March 25, 2022

Language: Английский

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The multifaceted role of ferroptosis in liver disease

Cell Death and Differentiation, Journal Year: 2022, Volume and Issue: 29(3), P. 467 - 480

Published: Jan. 24, 2022

Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by excessive lipid peroxidation and associated with a plethora pathological conditions in the liver. Emerging evidence supports notion that dysregulated metabolic pathways impaired iron homeostasis play role progression liver disease via ferroptosis. Although molecular mechanisms which ferroptosis causes are poorly understood, several ferroptosis-associated genes have been implicated disease. Here, we review physiological processing nutrients, our current understanding metabolism, characteristics ferroptosis, regulate In addition, summarize pathogenesis disease, including injury, non-alcoholic steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma. Finally, discuss therapeutic potential targeting for managing

Language: Английский

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

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 24(1), P. 449 - 449

Published: Dec. 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.

Language: Английский

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Programmed Cell Death Tunes Tumor Immunity

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: March 30, 2022

The demise of cells in various ways enables the body to clear unwanted cells. Studies over years revealed distinctive molecular mechanisms and functional consequences several key cell death pathways. Currently, most intensively investigated programmed (PCD) includes apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, autophagy, which has been discovered play crucial roles modulating immunosuppressive tumor microenvironment (TME) determining clinical outcomes cancer therapeutic approaches. PCD can dual roles, either pro-tumor or anti-tumor, partly depending on intracellular contents released during process. also regulates enrichment effector regulatory immune cells, thus participating fine-tuning anti-tumor immunity TME. In this review, we focused primarily discussed messengers regulating their intricate crosstalk with response TME, explored immunological consequence its implications future therapy developments.

Language: Английский

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Recent progress in ferroptosis: inducers and inhibitors

Cell Death Discovery, Journal Year: 2022, Volume and Issue: 8(1)

Published: Dec. 29, 2022

Ferroptosis is a new iron-dependent form of programmed cell death characterized by iron accumulation and lipid peroxidation. In recent years, ferroptosis has garnered enormous interest in disease treatment research communities pursuit to reveal the mechanism key targets because closely related pathophysiological processes many diseases. Recent studies have shown some targets, such as glutathione peroxidase 4 (GPX4) System Xc-, several inducers inhibitors been developed regulate these targets. With emergence on made developments. The selection use are very important for work. This paper briefly introduces regulatory metabolic pathway, lists categorizes commonly used recently inhibitors, discusses their medical application. ends with potential future direction ferroptosis.

Language: Английский

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The diversified role of mitochondria in ferroptosis in cancer

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(8)

Published: Aug. 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.

Language: Английский

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YAP1 alleviates sepsis-induced acute lung injury via inhibiting ferritinophagy-mediated ferroptosis

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 1, 2022

Ferroptosis is a phospholipid peroxidation-mediated and iron-dependent cell death form, involved in sepsis-induced organ injury other lung diseases. Yes-associated protein 1 (YAP1), key regulator of the Hippo signaling pathway, could target multiple ferroptosis regulators. Herein, this study aimed to explore involvement etiopathogenesis acute (ALI) demonstrate that YAP1 disrupt ferritinophagy moderate ALI. Cecal ligation puncture (CLP) models were constructed wild-type (WT) pulmonary epithelium-conditional knockout (YAP1 f/f ) mice induce ALI, while MLE-12 cells with or without overexpression stimulated by lipopolysaccharide (LPS) vitro . In-vivo modes showed aggravated CLP-induced ALI also accelerated ferroptosis, as presented downregulated expression GPX4, FTH1, SLC7A11, along upregulated SFXN1 NCOA4. Transcriptome research identified these genes pathways In-vitro consistently verified deficiency boosted ferrous iron accumulation mitochondrial dysfunction response LPS. Furthermore, co-IP assay revealed prevent degradation ferritin mass Fe 2+ (ferritinophagy) via disrupting NCOA4–FTH1 interaction, which blocked transport cytoplasmic into mitochondria membrane (SFXN1), further reducing generation ROS. Therefore, findings inhibit ferritinophagy-mediated manner, thus alleviating may provide new approach therapeutic orientation for

Language: Английский

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The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities

Biomedicines, Journal Year: 2022, Volume and Issue: 10(4), P. 891 - 891

Published: April 13, 2022

The selenoprotein glutathione peroxidase 4 (GPX4) is one of the main antioxidant mediators in human body. Its central function involves reduction complex hydroperoxides into their respective alcohols often using reduced Glutathione (GSH) as a reducing agent. GPX4 has become hotspot therapeutic target biomedical research following its characterization chief regulator ferroptosis, and subsequent recognition specific pharmacological for treatment an extensive variety diseases including cancers neurodegenerative disorders. Several recent studies have provided insights how distinguished from rest family, unique biochemical properties GPX4, related to lipid peroxidation enzyme may be modulated potential target. This current report aims review literature underlying all these present up-to-date perspective on understanding

Language: Английский

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Targeting ferroptosis in acute kidney injury

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(2)

Published: Feb. 24, 2022

Acute kidney injury (AKI) is a major public health problem with high incidence and mortality. As form of programmed cell death (PCD), ferroptosis could be considered as process iron accumulation enhanced lipid peroxidation. Recently, the fundamental roles in AKI have attracted much attention. The network mechanism its to chronic disease (CKD) transition complicated multifactorial. Strategies targeting show great potential. Here, we review research progress on participation AKI. We hope that this work will provide clues for further studies

Language: Английский

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OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(11), P. 1875 - 1891.e7

Published: Sept. 15, 2022

Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies the oxidative phosphorylation (OXPHOS) system of mitochondria. Here, we demonstrate that cardiac-specific loss assembly factor Cox10 cytochrome c oxidase causes cardiomyopathy mice, which is associated with OXPHOS deficiency, lysosomal defects, an aberrant morphology. Activation peptidase Oma1 Cox10−/− mice results fragmentation induction integrated stress response (ISR) along Oma1-Dele1-Atf4 signaling axis. Ablation or Dele1 aggravates cardiomyopathy. ISR inhibition impairs cardiac glutathione metabolism, limits selenium-dependent accumulation peroxidase Gpx4, increases lipid peroxidation heart, ultimately culminating ferroptosis. Our a protective role Oma1-Dele1-mediated link ferroptosis to deficiency disease.

Language: Английский

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