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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Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

Medicinal Research Reviews, Journal Year: 2023, Volume and Issue: 43(3), P. 614 - 682

Published: Jan. 19, 2023

Abstract Ferroptosis is an iron‐dependent cell death program that characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions structural features of ferroptosis‐inducing compounds might therefore open door efficient pharmacological strategies against aggressive, metastatic, therapy‐resistant cancer. We here summarize mechanisms requirements small molecules target central players ferroptosis. Focus placed on (i) glutathione peroxidase (GPX) 4, only GPX isoenzyme detoxifies complex membrane‐bound hydroperoxides, (ii) cystine/glutamate antiporter system X c − for regeneration, (iii) redox‐protective transcription factor nuclear erythroid 2‐related (NRF2), (iv) GPX4 repression combination with induced heme degradation via oxygenase‐1. deduce common ferroptotic activity highlight challenges development. Moreover, we critically discuss potential natural products lead structures provide comprehensive overview structurally diverse biogenic bioinspired trigger iron oxidation, inhibition thioredoxin/thioredoxin reductase or less defined modes action.

Language: Английский

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Cellular metabolism: A key player in cancer ferroptosis

Cancer Communications, Journal Year: 2024, Volume and Issue: 44(2), P. 185 - 204

Published: Jan. 13, 2024

Abstract Cellular metabolism is the fundamental process by which cells maintain growth and self‐renewal. It produces energy, furnishes raw materials, intermediates for biomolecule synthesis, modulates enzyme activity to sustain normal cellular functions. foundation of life processes plays a regulatory role in various biological functions, including programmed cell death. Ferroptosis recently discovered form iron‐dependent The inhibition ferroptosis crucial tumorigenesis tumor progression. However, metabolism, particularly glucose amino acid cancer not well understood. Here, we reviewed glucose, lipid, acid, iron selenium involvement elucidate impact different metabolic pathways on this process. Additionally, provided detailed overview agents used induce ferroptosis. We explained that maintaining intracellular redox homeostasis disrupting these renders them more susceptible iron‐induced death, resulting enhanced killing. combination inducers inhibitors may be novel approach future therapy an important strategy advance development treatments.

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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Regulation and targeting of SREBP-1 in hepatocellular carcinoma

Cancer and Metastasis Reviews, Journal Year: 2023, Volume and Issue: 43(2), P. 673 - 708

Published: Dec. 1, 2023

Abstract Hepatocellular carcinoma (HCC) is an increasing burden on global public health and associated with enhanced lipogenesis, fatty acid uptake, lipid metabolic reprogramming. De novo lipogenesis under the control of transcription factor sterol regulatory element-binding protein 1 (SREBP-1) essentially contributes to HCC progression. Here, we summarize current knowledge regulation SREBP-1 isoforms in based cellular, animal, clinical data. Specifically, (i) address overarching mechanisms for regulating transcription, proteolytic processing, nuclear stability, transactivation (ii) critically discuss their impact HCC, taking into account (iii) insights from pharmacological approaches. Emphasis placed cross-talk phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mechanistic target rapamycin (mTOR) axis, AMP-activated (AMPK), A (PKA), other kinases that directly phosphorylate SREBP-1; factors, such as liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), γ co-activator (PGC-1), signal transducers activators (STATs), Myc; epigenetic mechanisms; post-translational modifications SREBP-1-regulatory metabolites oxysterols polyunsaturated acids. By carefully scrutinizing role development, progression, metastasis, therapy resistance, shed light potential SREBP-1-targeting strategies prevention treatment.

Language: Английский

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Oxytosis/Ferroptosis in Neurodegeneration: the Underlying Role of Master Regulator Glutathione Peroxidase 4 (GPX4)

Molecular Neurobiology, Journal Year: 2023, Volume and Issue: 61(3), P. 1507 - 1526

Published: Sept. 19, 2023

Language: Английский

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Role of oxidative stress‐induced ferroptosis in cancer therapy

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(10)

Published: May 1, 2024

Abstract Ferroptosis is a distinct mode of cell death, distinguishing itself from typical apoptosis by its reliance on the accumulation iron ions and lipid peroxides. Cells manifest an imbalance between oxidative stress antioxidant equilibrium during certain pathological contexts, such as tumours, resulting in stress. Notably, recent investigations propose that heightened intracellular reactive oxygen species (ROS) due to can heighten cellular susceptibility ferroptosis inducers or expedite onset ferroptosis. Consequently, comprehending role ROS initiation has significance elucidating disorders related Moreover, exhaustive exploration into mechanism control might offer novel targets for addressing specific tumour types. Within this context, our review delves fundamental pathways molecular foundation Four classical ferroptotic are well characterized, namely, glutathione peroxidase 4‐centred pathway, nuclear factor erythroid 2‐related 2 mitochondrial mTOR‐dependent autophagy pathway. Furthermore, we seek elucidate regulatory contributions enacted ROS. Additionally, provide overview targeted medications targeting four implicated their potential clinical applications. Here, ferroptosis, discuss opportunities use new strategy cancer therapy point out current challenges persisting within domain ROS‐regulated anticancer drug research development.

Language: Английский

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Gamma-oryzanol alleviates osteoarthritis development by targeting Keap1–Nrf2 binding to interfere with chondrocyte ferroptosis

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 128, P. 111469 - 111469

Published: Jan. 10, 2024

Language: Английский

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Recent advancements in nanomaterial-mediated ferroptosis-induced cancer therapy: Importance of molecular dynamics and novel strategies

Life Sciences, Journal Year: 2024, Volume and Issue: 346, P. 122629 - 122629

Published: April 15, 2024

Ferroptosis is a novel type of controlled cell death resulting from an imbalance between oxidative harm and protective mechanisms, demonstrating significant potential in combating cancer. It differs other forms death, such as apoptosis necrosis. Molecular therapeutics have hard time playing the long-acting role ferroptosis induction due to their limited water solubility, low targeting capacity, quick metabolism vivo. To this end, small molecule inducers based on biological factors long been used strategy induce death. Research into advancements nanotechnology led discovery that nanomaterials are superior medications triggering ferroptosis. Nanomaterials derived iron can enhance by directly releasing large quantities increasing ROS levels. Moreover, utilizing promote programmed minimizes probability unfavorable effects induced mutations cancer-associated genes RAS TP53. Taken together, review summarizes molecular mechanisms involved along with classification induction. also emphasized importance organelles control cancer therapy. The trigger categorized explained. Iron-based noniron-based characterization at cellular levels explored, which will be useful for inducing leads reduced tumor growth. Within framework, we offer synopsis, traverses well-established mechanism offers practical suggestions design therapeutic use nanomaterials.

Language: Английский

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Antioxidant Enzymes and Their Potential Use in Breast Cancer Treatment

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 5675 - 5675

Published: May 23, 2024

According to the World Health Organization (WHO), breast cancer (BC) is deadliest and most common type of worldwide in women. Several factors associated with BC exert their effects by modulating state stress. They can induce genetic mutations or alterations cell growth, encouraging neoplastic development production reactive oxygen species (ROS). ROS are able activate many signal transduction pathways, producing an inflammatory environment that leads suppression programmed death promotion tumor proliferation, angiogenesis, metastasis; these promote progression malignant neoplasms. However, cells have both non-enzymatic enzymatic antioxidant systems protect them neutralizing harmful ROS. In this sense, enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reductase (GR), thioredoxin (TrxR), peroxiredoxin (Prx) body from diseases caused oxidative damage. review, we will discuss mechanisms through which some antioxidants inhibit carcinogenesis, well new therapeutic proposals developed complement traditional treatments.

Language: Английский

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