Ferroptosis as a potential target for cancer therapy

Cell Death and Disease, Год журнала: 2023, Номер 14(7)

Опубликована: Июль 24, 2023

Abstract Ferroptosis is a recently discovered essential type of cell death that mainly characterized by iron overload and lipid peroxidation. Emerging evidence suggests ferroptosis double-edged sword in human cancer. However, the precise underlying molecular mechanisms their differential roles tumorigenesis are unclear. Therefore, this review, we summarize briefly present key pathways ferroptosis, paying special attention to regulation as well its dual role an oncogenic tumor suppressor event various cancers. Moreover, multiple pharmacological activators summarized, prospect targeting cancer therapy further elucidated.

Язык: Английский

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Ferroptosis in health and disease

Redox Biology, Год журнала: 2024, Номер 75, С. 103211 - 103211

Опубликована: Май 30, 2024

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark ferroptosis uncontrolled overwhelming peroxidation polyunsaturated fatty acids contained membrane phospholipids, which eventually leads to rupture the plasma membrane. unique that it essentially spontaneous, uncatalyzed chemical process based on perturbed iron redox homeostasis contributing process, but nonetheless modulated by many metabolic nodes impinge cells' susceptibility ferroptosis. Among affecting sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets treatment numerous currently incurable diseases. Herein, current members Germany-wide research consortium focusing research, well key external experts who made seminal contributions this rapidly growing exciting field gathered provide comprehensive, state-of-the-art review Specific topics include: basic mechanisms, vivo relevance, specialized methodologies, tools, potential contribution disease etiopathology progression. We hope article will not only established scientists newcomers with an overview multiple facets ferroptosis, also encourage additional efforts characterize further molecular pathways modulating ultimate goal develop novel pharmacotherapies tackle associated - or caused

Язык: Английский

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Melatonin protects against cadmium-induced endoplasmic reticulum stress and ferroptosis through activating Nrf2/HO-1 signaling pathway in mice lung

Food and Chemical Toxicology, Год журнала: 2025, Номер unknown, С. 115324 - 115324

Опубликована: Фев. 1, 2025

Язык: Английский

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Salidroside ameliorates acetaminophen-induced acute liver injury through the inhibition of endoplasmic reticulum stress-mediated ferroptosis by activating the AMPK/SIRT1 pathway

Ecotoxicology and Environmental Safety, Год журнала: 2023, Номер 262, С. 115331 - 115331

Опубликована: Авг. 7, 2023

Acetaminophen (APAP) overdose has long been considered a major cause of drug-induced liver injury. Ferroptosis is type programmed cell death mediated by iron-dependent lipid peroxidation. Endoplasmic reticulum (ER) stress systemic response triggered the accumulation unfolded or misfolded proteins in ER. and ER have proven to contribute progression APAP-induced acute injury (ALI). It was reported that salidroside protects against ALI, but potential mechanism remain unknown. In this study, male C57BL/6 J mice were intraperitoneally (i.p.) injected APAP (500 mg/kg) induce an ALI model. Salidroside i.p. at dose 100 mg/kg 2 h prior administration. Mice sacrificed 12 after injection serum obtained for histological biochemistry analysis. AML12 cells used vitro assays. The results indicated mitigated glutathione degradation via inhibiting cation transport regulator homolog 1 (CHAC1) attenuate ferroptosis, simultaneously suppressing PERK-eIF2α-ATF4 axis-mediated stress, thus alleviating ALI. However, PERK activator CCT020312 overexpression ATF4 inhibited protective function on CHAC1-mediated ferroptosis. Besides this, activation AMPK/SIRT1 signaling pathway demonstrated effect Interestingly, selective inhibition SIRT1 ameliorated effects Overall, plays significant part mitigation activating inhibit stress-mediated ferroptosis ATF4-CHAC1 axis.

Язык: Английский

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The molecular mechanisms and potential drug targets of ferroptosis in myocardial ischemia–reperfusion injury

Life Sciences, Год журнала: 2024, Номер 340, С. 122439 - 122439

Опубликована: Янв. 24, 2024

Myocardial ischemia–reperfusion injury (MIRI), caused by the initial interruption and subsequent restoration of coronary artery blood, results in further damage to cardiac function, affecting prognosis patients with acute myocardial infarction. Ferroptosis is an iron-dependent, superoxide-driven, non-apoptotic form regulated cell death that involved pathogenesis MIRI. characterized accumulation lipid peroxides (LOOH) redox disequilibrium. Free iron ions can induce oxidative stress as a substrate Fenton reaction lipoxygenase (LOX) participate inactivation variety antioxidants including CoQ10 GPX4, destroying balance causing death. The metabolism amino acid, iron, lipids, associated pathways, considered specific hallmark ferroptosis. This review systematically summarizes latest research progress on mechanisms ferroptosis discusses analyzes therapeutic approaches targeting alleviate

Язык: Английский

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Targeting ferroptosis in autoimmune diseases: Mechanisms and therapeutic prospects

Autoimmunity Reviews, Год журнала: 2024, Номер unknown, С. 103640 - 103640

Опубликована: Сен. 1, 2024

Язык: Английский

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GPR68-ATF4 signaling is a novel prosurvival pathway in glioblastoma activated by acidic extracellular microenvironment

Experimental Hematology and Oncology, Год журнала: 2024, Номер 13(1)

Опубликована: Янв. 31, 2024

Abstract Background Glioblastoma multiforme (GBM) stands as a formidable challenge in oncology because of its aggressive nature and severely limited treatment options. Despite decades research, the survival rates for GBM remain effectively stagnant. A defining hallmark is highly acidic tumor microenvironment, which thought to activate pro-tumorigenic pathways. This acidification result altered metabolism favoring aerobic glycolysis, phenomenon known Warburg effect. Low extracellular pH confers radioresistant tumors glial cells. Notably GPR68, an acid sensing GPCR, upregulated GBM. Usage Lorazepam, has off target agonism linked worse clinical outcomes variety cancers. However, role microenvironment GPR68 activation not been assessed cancer. Here we interrogate specifically cells using novel specific small molecule inhibitor named Ogremorphin (OGM) induce iron mediated cell death pathway: ferroptosis. Method OGM was identified non-biased zebrafish embryonic development screen validated with Morpholino CRISPR based approaches. Next, GPI-anchored reporter, pHluorin2, stably expressed U87 glioblastoma probe acidification. Cell assays, via nuclei counting titer glo, were used demonstrate sensitivity inhibition twelve immortalized PDX lines. To determine inhibition’s mechanism use DAVID pathway analysis RNAseq. Our major indication, ferroptosis, then confirmed by western blotting qRT-PCR reporter genes including TFRC. finding further transmission electron microscopy liperfluo staining assess lipid peroxidation. Lastly, siRNA CRISPRi critical ATF4 suppression survival. Results We pHLourin2 how acidify their commonly over GPR68. Using our genetic means, show that blocking signaling results robust all thirteen lines tested, irrespective phenotypic heterogeneity, or resistance mainstay chemotherapeutic temozolomide. U138 selective induction ferroptosis occurs ATF4-dependent manner. Importantly, not-acutely toxic inhibitory effects found spare non-malignant neural Conclusion These indicate emerges sensor autocrine cascade triggered In this context, suppresses ATF4, increases expression leads ferroptotic death. findings provide promising therapeutic approach selectively while sparing healthy tissue.

Язык: Английский

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Dysregulation of iron homeostasis and ferroptosis in sevoflurane and isoflurane associated perioperative neurocognitive disorders

CNS Neuroscience & Therapeutics, Год журнала: 2024, Номер 30(2)

Опубликована: Фев. 1, 2024

In recent years, sevoflurane and isoflurane are the most popular anesthetics in general anesthesia for their safe, rapid onset, well tolerant. Nevertheless, many studies reported neurotoxicity among pediatric aged populations. This effect is usually manifested as cognitive impairment such perioperative neurocognitive disorders. The wide application of during makes safety a major health concern. Evidence indicates that iron dyshomeostasis ferroptosis may establish role isoflurane. However, mechanisms sevoflurane- isoflurane-induced neuronal injury were not fully understood, which poses barrier to treatment its neurotoxicity. We, therefore, reviewed current knowledge on aimed promote better understanding roles

Язык: Английский

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Sevoflurane Postconditioning Attenuates Cerebral Ischemia-Reperfusion Injury by Inhibiting SP1/ACSL4-Mediated Ferroptosis

Human & Experimental Toxicology, Год журнала: 2023, Номер 42

Опубликована: Фев. 26, 2023

Sevoflurane is the most commonly used anesthetic in clinical practice and exerts a protective effect on cerebral ischemia-reperfusion (I/R) injury. This study aims to elucidate molecular mechanism by which sevoflurane postconditioning protects against I/R Oxygen-glucose deprivation/reperfusion (OGD/R) model vitro middle artery occlusion (MCAO) vivo were established simulate reduced neurological deficits, infarction, ferroptosis after Interestingly, significantly inhibited specificity protein 1 (SP1) expression MACO rats HT22 cells exposed OGD/R. SP1 overexpression attenuated neuroprotective effects of OGD/R-treated cells, evidenced cell viability, increased apoptosis, cleaved caspase-3 expression. Furthermore, chromatin immunoprecipitation luciferase experiments verified that bound directly ACSL4 promoter region increase its In addition, via SP1/ACSL4 axis. Generally, our describes an anti-ferroptosis injury downregulating SP1/ASCL4 These findings suggest novel sight for protection indicate potential therapeutic approach variety diseases.

Язык: Английский

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Glutathione‑degrading enzymes in the complex landscape of tumors (Review)

International Journal of Oncology, Год журнала: 2024, Номер 65(1)

Опубликована: Июнь 3, 2024

Glutathione (GSH)‑degrading enzymes are essential for starting the first stages of GSH degradation. These include extracellular γ‑glutamyl transpeptidase (GGT) and intracellular GSH‑specific γ‑glutamylcyclotransferase 1 (ChaC1) 2. cellular activities, such as immune response, differentiation, proliferation, homeostasis regulation programmed cell death. Tumor tissue frequently exhibits abnormal expression GSH‑degrading enzymes, which has a key impact on development spread malignancies. The present review summarizes gene protein structure, catalytic activity their vital roles in tumor (including oxidative endoplasmic reticulum stress, control death, promotion inflammation tumorigenesis modulation drug resistance cells) potential role diagnostic biomarkers therapeutic targets.

Язык: Английский

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