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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Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Sept. 12, 2023

Abstract Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen nutrients, tumor cells undergo transformations exploit various ways acquiring lipid increasing oxidation. addition, stromal immune the microenvironment also reprogramming, which further affects functional phenotypes responses. Given metabolism plays a critical role supporting cancer progression remodeling microenvironment, targeting pathway could provide novel approach treatment. This review seeks to: (1) clarify overall landscape mechanisms cancer, (2) summarize landscapes within their roles progression, (3) potential therapeutic targets for metabolism, highlight combining such approaches with other anti-tumor therapies new opportunities patients.

Language: Английский

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Mechanism of sorafenib resistance associated with ferroptosis in HCC

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: June 7, 2023

Hepatocellular carcinoma (HCC) is the most familiar primary hepatic malignancy with a poor prognosis. The incidence of HCC and associated deaths have risen in recent decades. Sorafenib first drug to be approved by Food Drug Administration (FDA) for routine use first-line therapy patients advanced HCC. However, only about 30% will benefited from sorafenib therapy, resistance typically develops within 6 months. In years, mechanisms gained attention growing number researchers. A promising field current studies ferroptosis, which novel form cell death differing apoptosis, necroptosis, autophagy. This process dependent on accumulation intracellular iron reactive oxygen species (ROS). Furthermore, increase levels ROS can significantly observed cells resistant sorafenib. article reviews that are related evaluates relationship between ferroptosis resistance, explores new therapeutic approaches capable reversing through modulation ferroptosis.

Language: Английский

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Cancer metabolism and carcinogenesis

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: Jan. 29, 2024

Abstract Metabolic reprogramming is an emerging hallmark of cancer cells, enabling them to meet increased nutrient and energy demands while withstanding the challenging microenvironment. Cancer cells can switch their metabolic pathways, allowing adapt different microenvironments therapeutic interventions. This refers heterogeneity, in which cell populations use pathways sustain survival proliferation impact response conventional therapies. Thus, targeting heterogeneity represents innovative avenue with potential overcome treatment resistance improve outcomes. review discusses patterns developmental stages, summarizes molecular mechanisms involved intricate interactions within metabolism, highlights clinical vulnerabilities as a promising regimen. We aim unravel complex characteristics develop personalized approaches address distinct traits, ultimately enhancing patient

Language: Английский

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Epigenetic regulation of diverse cell death modalities in cancer: a focus on pyroptosis, ferroptosis, cuproptosis, and disulfidptosis

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: April 23, 2024

Abstract Tumor is a local tissue hyperplasia resulted from cancerous transformation of normal cells under the action various physical, chemical and biological factors. The exploration tumorigenesis mechanism crucial for early prevention treatment tumors. Epigenetic modification common important in cells, including DNA methylation, histone modification, non-coding RNA m6A modification. mode cell death programmed by death-related genes; however, recent researches have revealed some new modes death, pyroptosis, ferroptosis, cuproptosis disulfidptosis. regulation deaths mainly involved key proteins affects up-regulating or down-regulating expression levels proteins. This study aims to investigate epigenetic modifications regulating disulfidptosis tumor explore possible triggering factors development microscopic point view, provide potential targets therapy perspective antitumor drugs combination therapies.

Language: Английский

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Metabolism-regulated ferroptosis in cancer progression and therapy

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(3)

Published: March 8, 2024

Abstract Cancer metabolism mainly includes carbohydrate, amino acid and lipid metabolism, each of which can be reprogrammed. These processes interact with other to adapt the complicated microenvironment. Ferroptosis is a regulated cell death induced by iron-dependent peroxidation, morphologically different from apoptosis, necrosis, necroptosis, pyroptosis, autophagy-dependent cuprotosis. plays opposite roles in ferroptosis. On one hand, carbohydrate produce NADPH maintain GPX4 FSP1 function, provide substrates for synthesizing GPX4; on might synthesize PUFAs trigger The mechanisms through cancer affects ferroptosis have been investigated extensively long time; however, some not yet elucidated. In this review, we summarize interaction between Importantly, were most concerned how these targets utilized therapy.

Language: Английский

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Iron, Oxidative Stress, and Metabolic Dysfunction—Associated Steatotic Liver Disease

Antioxidants, Journal Year: 2024, Volume and Issue: 13(2), P. 208 - 208

Published: Feb. 7, 2024

Excess free iron is a substrate for the formation of reactive oxygen species (ROS), thereby augmenting oxidative stress. Oxidative stress well-established cause organ damage in liver, main site storage. Ferroptosis, an iron-dependent mechanism regulated cell death, has recently been gaining attention development and progression liver disease. We therefore summarize mechanisms metabolism, its close connection to ferroptosis, particular relevance disease metabolic-dysfunction-associated fatty potential targets therapy from clinical perspective.

Language: Английский

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Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: April 13, 2024

The dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood. Endoplasmic reticulum oxidoreductase alpha (ERO1α) expression mTORC1-activated mouse embryonic fibroblasts, cancer cells, laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence (IF), immunohistochemistry. Extensive vitro vivo experiments were carried out determine ERO1α its downstream target, member 11 solute carrier family 7 (SLC7A11), mTORC1-mediated proliferation, angiogenesis, resistance, tumor growth. regulatory mechanism on SLC7A11 investigated via RNA-sequencing, cytokine array, an enzyme-linked immunosorbent assay, qRT-PCR, IF, luciferase reporter chromatin immunoprecipitation assay. combined therapeutic effect inhibition inducer imidazole ketone erastin (IKE) cells evaluated using line-derived xenografts, LSCC organoids, patient-derived xenograft models. is functional mTORC1. Elevated induced exerted pro-oncogenic roles upregulation SLC7A11. Mechanically, stimulated transcription activating interleukin-6 (IL-6)/signal transducer activator 3 (STAT3) pathway. Moreover, with treatment IKE exhibited synergistic antitumor effects tumors. ERO1α/IL-6/STAT3/SLC7A11 pathway crucial for growth, combining inducers novel effective mTORC1-related

Language: Английский

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Oxidative Stress and Reprogramming of Lipid Metabolism in Cancers

Antioxidants, Journal Year: 2025, Volume and Issue: 14(2), P. 201 - 201

Published: Feb. 10, 2025

Oxidative stress is a common event involved in cancer pathophysiology, frequently accompanied by unique lipid metabolic reprogramming phenomena. caused mainly an imbalance between the production of reactive oxygen species (ROS) and antioxidant system cells. Emerging evidence has reported that oxidative regulates expression activity metabolism-related enzymes, leading to alteration cellular metabolism; this involves significant increase fatty acid synthesis shift way which lipids are taken up utilized. The dysregulation metabolism provides abundant intermediates synthesize biological macromolecules for rapid proliferation cells; moreover, it contributes maintenance intracellular redox homeostasis producing variety reducing agents. Moreover, derivatives metabolites play critical roles signal transduction within cells tumor microenvironment evades immune destruction facilitates invasion metastasis. These findings suggest close relationship during malignant progression cancers. This review focuses on crosstalk reprogramming, in-depth insight into modulation ROS cancers discusses potential strategies targeting therapy.

Language: Английский

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Epigenetically upregulated NSUN2 confers ferroptosis resistance in endometrial cancer via m5C modification of SLC7A11 mRNA

Redox Biology, Journal Year: 2023, Volume and Issue: 69, P. 102975 - 102975

Published: Nov. 29, 2023

Endometrial cancer (EC) is a prevalent gynecological malignancy worldwide, and 5-methylcytosine (m5C) modification of mRNA crucial epigenetic associated with the development occurrence several cancers. However, precise function m5C in EC remains elusive. This study aimed to investigate expression clinical significance primary writer, NSUN2, EC. Our findings indicated that NSUN2 exhibited substantial up-regulation as result an augmentation H3K4me3 levels within promoter region, which was triggered by down-regulation KDM5A. Moreover, gain- loss-of-function experiments revealed role enhancing mRNA, thereby promoting cell proliferation. RNA bisulfite sequencing transcriptomic were employed elucidate involvement regulation ferroptosis. Subsequent vitro confirmed knockdown significantly up-regulated lipid peroxides ROS cells, augmenting susceptibility Mechanistically, stimulated SLC7A11 reader YBX1 direct recognition binding sites on via its internal cold shock domain (CSD), leading increase stability elevated SLC7A11. Additionally, rescue showed functioned suppressor ferroptosis, dependent Overall, targeting NSUN2/SLC7A11 axis inhibited tumor growth increasing peroxidation ferroptosis cells both vivo. Therefore, our provides new insight into suggesting may serve prognostic biomarker therapeutic target patients

Language: Английский

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