Ferroptosis: molecular mechanisms and health implications

Cell Research, Journal Year: 2020, Volume and Issue: 31(2), P. 107 - 125

Published: Dec. 2, 2020

Abstract Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form non-apoptotic cell in 2012, there has been mounting interest process and function ferroptosis. Ferroptosis occur two major pathways, extrinsic or transporter-dependent pathway intrinsic enzyme-regulated pathway. is caused by a redox imbalance between production oxidants antioxidants, which driven abnormal expression activity multiple redox-active enzymes that produce detoxify free radicals lipid oxidation products. Accordingly, precisely regulated at levels, including epigenetic, transcriptional, posttranscriptional posttranslational layers. The transcription factor NFE2L2 plays central role upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on integrated molecular machinery describe how dysregulated involved cancer, neurodegeneration, tissue injury, inflammation, infection.

Language: Английский

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Broadening horizons: the role of ferroptosis in cancer

Nature Reviews Clinical Oncology, Journal Year: 2021, Volume and Issue: 18(5), P. 280 - 296

Published: Jan. 29, 2021

Language: Английский

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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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Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 20, 2022

Abstract In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not ICIs, partly caused absence of tumor-infiltrating lymphocytes (TILs), significantly limits application ICIs. Converting these “cold” into “hot” may ICIs is an unsolved question immunotherapy. Since it a general characteristic cancers resist apoptosis, induction non-apoptotic regulated cell death (RCD) emerging as new treatment strategy. Recently, several studies have revealed interaction between RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, necroptosis exhibit synergistic responses while possibly exerting inhibitory effects on responses. Thus, targeted therapies (inducers inhibitors) against combination with exert potent activity, resistant This review summarizes multilevel relationship immunity RCD, including necroptosis, potential targeting improve efficacy malignancy.

Language: Английский

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Ferroptosis in infection, inflammation, and immunity

The Journal of Experimental Medicine, Journal Year: 2021, Volume and Issue: 218(6)

Published: May 12, 2021

Ferroptosis is a type of regulated necrosis that triggered by combination iron toxicity, lipid peroxidation, and plasma membrane damage. The upstream inducers ferroptosis can be divided into two categories (biological versus chemical) activate major pathways (the extrinsic/transporter the intrinsic/enzymatic pathways). Excessive or deficient ferroptotic cell death implicated in growing list physiological pathophysiological processes, coupled to dysregulated immune response. This review focuses on new discoveries related how cells their spilled contents shape innate adaptive immunity health disease. Understanding immunological characteristics activity not only illuminates an intersection between but may also lead development novel treatment approaches for immunopathological diseases.

Language: Английский

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Cellular degradation systems in ferroptosis

Cell Death and Differentiation, Journal Year: 2021, Volume and Issue: 28(4), P. 1135 - 1148

Published: Jan. 18, 2021

Language: Английский

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Signaling pathways and defense mechanisms of ferroptosis

FEBS Journal, Journal Year: 2021, Volume and Issue: 289(22), P. 7038 - 7050

Published: June 6, 2021

As a type of lytic cell death driven by unrestricted lipid peroxidation and subsequent plasma membrane damage, ferroptosis occurs develops because sophisticated signals regulatory mechanisms. The reactive oxygen species (ROS) used to initiate come from variety sources, including iron‐mediated Fenton reactions, mitochondrial ROS, membrane‐associated ROS the NOX protein family. Polyunsaturated fatty acid‐containing phospholipids are main substrates in ferroptosis, which is positively regulated enzymes, such as ACSL4, LPCAT3, ALOXs, or POR. Selective activation autophagic degradation pathways promotes increasing iron accumulation cause peroxidation. In contrast, system xc – ‐glutathione–GPX4 axis plays central role limiting peroxidation, although other antioxidants (such coenzyme Q10 tetrahydrobiopterin) can also inhibit ferroptosis. A nuclear mechanism defense against NFE2L2‐dependent antioxidant response transcriptionally upregulating expression cytoprotective genes. Additionally, damage caused ferroptotic stimulus be repaired ESCRT‐III‐dependent scission machinery. this review, we summarize recent progress understanding signaling mechanisms

Language: Английский

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Mitochondrial regulation of ferroptosis

The Journal of Cell Biology, Journal Year: 2021, Volume and Issue: 220(9)

Published: July 30, 2021

Ferroptosis is a form of iron-dependent regulated cell death driven by uncontrolled lipid peroxidation. Mitochondria are double-membrane organelles that have essential roles in energy production, cellular metabolism, and regulation. However, their role ferroptosis has been unclear somewhat controversial. In this Perspective, I summarize the diverse metabolic processes mitochondria actively drive ferroptosis, discuss recently discovered mitochondria-localized defense systems detoxify mitochondrial peroxides protect against present new evidence for regulating outline outstanding questions on fascinating topic future investigations. An in-depth understanding functions will important implications both fundamental biology disease treatment.

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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Characteristics and Biomarkers of Ferroptosis

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Jan. 21, 2021

The induction and consequences of regulated cell death (RCD) are accompanied by changes in gene protein expression, biochemical pathways, as well morphology size. Such RCDs have a significant impact on development, tissue homeostasis, the occurrence progression disease. Among different forms RCD, ferroptosis appears to be main cause damage driven iron overload lipid peroxidation. In fact, dysfunctional ferroptotic response is implicated variety pathological conditions diseases, such neurodegenerative ischemia-reperfusion injury, tumorigenesis, infections, immune diseases. Ferroptotic can fine-tuned through various oxidative stress antioxidant defense coupling with metabolism, transcription, degradation machinery. Accordingly, series inducers or inhibitors targeting redox- metabolism-related proteins signal transduction been developed. Although this kind RCD has recently attracted great interest basic clinical research, detecting monitoring still faces challenges. mini-review, we not only summarize latest knowledge about characteristics vitro vivo , but also discuss specificity limitations current biomarkers ferroptosis.

Language: Английский

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