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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Ferroptotic therapy in cancer: benefits, side effects, and risks

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 3, 2024

Abstract Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture intracellular content release. Originally investigated as targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential complement chemotherapy, immunotherapy, radiotherapy in various types. However, it can lead side effects, including immune death, bone marrow impairment, liver kidney damage, cachexia (severe weight loss muscle wasting), secondary tumorigenesis. In this review, we discuss the advantages offer an overview diverse range documented effects. Furthermore, examine underlying mechanisms explore strategies effect mitigation.

Language: Английский

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PRMT3‐Mediated Arginine Methylation of METTL14 Promotes Malignant Progression and Treatment Resistance in Endometrial Carcinoma

Advanced Science, Journal Year: 2023, Volume and Issue: 10(36)

Published: Nov. 16, 2023

Abstract Protein arginine methyltransferase (PRMT) plays essential roles in tumor initiation and progression, but its underlying mechanisms the treatment sensitivity of endometrial cancer (EC) remain unclear warrant further investigation. Here, a comprehensive analysis Cancer Genome Atlas database Clinical Proteomic Tumor Analysis Consortium identifies that PRMT3 an important role EC. Specifically, experiments show inhibition enhances susceptibility EC cells to ferroptosis. Mechanistically, interacts with Methyltransferase 14 (METTL14) is involved methylation. In addition, inhibition‐mediated METTL14 overexpression promotes methylation modification via m 6 A‐YTHDF2‐dependent mechanism, reducing Glutathione peroxidase 4 (GPX4) mRNA stability, increasing lipid peroxidation levels, accelerating Notably, combined blockade anti‐PD‐1 therapy display more potent antitumor effects by ferroptosis cell‐derived xenograft models. The specific inhibitor SGC707 exerts same immunotherapeutic sensitizing effect patient‐derived model. blocking improves suppression response cisplatin radiation therapy. Altogether, this work demonstrates depletion promising target for

Language: Английский

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Ferroptosis: the emerging player in remodeling triple-negative breast cancer

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

Published: Oct. 20, 2023

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor type that malignant, invasive, and recurrent. Ferroptosis unique mode of programmed cell death (PCD) at the morphological, physiological, molecular levels, mainly characterized by induced iron-dependent accumulation lipid peroxides, which plays substantial role in variety diseases, including tumors inflammatory diseases. TNBC cells have been reported to display peculiar equilibrium metabolic profile iron glutathione, may increase sensitivity ferroptosis. possesses higher ferroptosis than other types. also occurred between immune cells, suggesting regulating remodel modulating response. Many ferroptosis-related genes or molecules characteristic expression patterns are expected be diagnostic targets for TNBC. Besides, therapeutic strategies based on ferroptosis, isolation extraction natural drugs use inducers, urgent personalized treatment. Thus, this review will explore contribution progression, diagnosis, treatment, provide novel perspectives management.

Language: Английский

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Post-translational modifications of Keap1: the state of the art

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 11

Published: Jan. 8, 2024

The Keap1-Nrf2 signaling pathway plays a crucial role in cellular defense against oxidative stress-induced damage. Its activation entails the expression and transcriptional regulation of several proteins involved detoxification antioxidation processes within organism. Keap1, serving as pivotal regulator this pathway, exerts control over activity Nrf2. Various post-translational modifications (PTMs) such alkylation, glycosylation, glutathiylation, S-sulfhydration, other modifications, impact binding affinity between Keap1 Consequently, leads to accumulation Nrf2 its translocation nucleus, subsequent downstream antioxidant genes. Given association various diseases cancer, neurodegenerative disorders, diabetes, comprehending modification not only deepens our understanding but also contributes identification novel drug targets biomarkers. knowledge holds immense importance prevention treatment induced by stress.

Language: Английский

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Ferroptosis: mechanisms and therapeutic targets

MedComm, Journal Year: 2024, Volume and Issue: 5(12)

Published: Nov. 20, 2024

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation in membrane phospholipids. Since its identification 2012, extensive research has unveiled involvement the pathophysiology numerous diseases, including cancers, neurodegenerative disorders, organ injuries, infectious autoimmune conditions, metabolic and skin diseases. Oxidizable lipids, overload iron, compromised antioxidant systems are known as critical prerequisites for driving overwhelming peroxidation, ultimately leading to plasma rupture ferroptotic death. However, precise regulatory networks governing ferroptosis ferroptosis-targeted therapy these diseases remain largely undefined, hindering development pharmacological agonists antagonists. In this review, we first elucidate core mechanisms summarize epigenetic modifications (e.g., histone modifications, DNA methylation, noncoding RNAs, N6-methyladenosine modification) nonepigenetic genetic mutations, transcriptional regulation, posttranslational modifications). We then discuss association between disease pathogenesis explore therapeutic approaches targeting ferroptosis. also introduce potential clinical monitoring strategies Finally, put forward several unresolved issues which progress needed better understand hope review will offer promise application therapies context human health disease.

Language: Английский

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Exploring the role of metabolic pathways in TNBC immunotherapy: insights from single-cell and spatial transcriptomics

Frontiers in Endocrinology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 9, 2025

The article provides an overview of the current understanding interplay between metabolic pathways and immune function in context triple-negative breast cancer (TNBC). It highlights recent advancements single-cell spatial transcriptomics technologies, which have revolutionized analysis tumor heterogeneity microenvironment TNBC. review emphasizes crucial role reprogramming modulating cell function, discussing how specific pathways, such as glycolysis, lipid metabolism, amino acid can directly impact activity phenotypes various populations within TNBC microenvironment. Furthermore, explores implications these metabolic-immune interactions for efficacy checkpoint inhibitor (ICI) therapies TNBC, suggesting that strategies targeting may enhance responsiveness to ICI treatments. Finally, outlines future directions potential combination integrate modulation with immunotherapeutic approaches, offering promising avenues improving clinical outcomes patients.

Language: Английский

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Protein arginine methyltransferases (PRMTs): Orchestrators of cancer pathogenesis, immunotherapy dynamics, and drug resistance

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 221, P. 116048 - 116048

Published: Feb. 10, 2024

Language: Английский

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Ferroptosis and the tumor microenvironment

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

Published: Nov. 30, 2024

Abstract Ferroptosis is a type of regulated cell death characterized by its non-apoptotic, iron-dependent and oxidative nature. Since discovery in 2012, extensive research has demonstrated pivotal roles tumorigenesis, metastasis cancer therapy. The tumor microenvironment (TME) complex ecosystem comprising cells, non-cancer extracellular matrix, metabolites cytokines. Recent studies have underscored new paradigm which cells the TME, such as immune stromal also play significant regulating progression therapeutic resistance typically through complicated crosstalk with cells. Notably, this TME were partially mediated ferrotopsis-related mechanisms. This review provides comprehensive systematic summary current findings concerning ferroptosis how ferroptosis-mediated reprogramming impacts progression. Additionally, outlines various ferroptosis-related strategies aimed at targeting TME.

Language: Английский

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Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS/STING signaling

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 10, 2024

Abstract Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) driver immunotherapy in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1 signaling pathway, higher levels correlate with reduced numbers of tumor-infiltrating CD8 + poorer response ICB. Genetic depletion or pharmacological inhibition elicits influx into tumors reduces tumor size HCC mouse models. Mechanistically, methylates HSP60 at R446 induce oligomerization maintain mitochondrial homeostasis. Targeting PRMT3-dependent methylation disrupts integrity increases DNA (mtDNA) leakage, which results cGAS/STING-mediated anti-tumor immunity. Lastly, blocking functions synergize PD-1 Our study thus identifies potential biomarker target overcome

Language: Английский

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