The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity

Cell Reports, Journal Year: 2021, Volume and Issue: 35(11), P. 109235 - 109235

Published: June 1, 2021

T regulatory (Treg) cells are crucial to maintain immune tolerance and repress antitumor immunity, but the mechanisms governing their cellular redox homeostasis remain elusive. We report that glutathione peroxidase 4 (Gpx4) prevents Treg from lipid peroxidation ferroptosis in regulating immunity. Treg-specific deletion of Gpx4 impairs without substantially affecting survival at steady state. Loss results excessive accumulation peroxides upon cell receptor (TCR)/CD28 co-stimulation. Neutralization blockade iron availability rescue Gpx4-deficient cells. Moreover, elevate generation mitochondrial superoxide production interleukin-1β (IL-1β) facilitates helper 17 (T

Language: Английский

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Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy

Free Radical Biology and Medicine, Journal Year: 2020, Volume and Issue: 162, P. 435 - 449

Published: Nov. 2, 2020

Language: Английский

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Ferroptosis in Cancer Cell Biology

Cancers, Journal Year: 2020, Volume and Issue: 12(1), P. 164 - 164

Published: Jan. 9, 2020

A major hallmark of cancer is successful evasion regulated forms cell death. Ferroptosis a recently discovered type necrosis which, unlike apoptosis or necroptosis, independent caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, process which antagonised by glutathione peroxidase 4 (GPX4) ferroptosis suppressor (FSP1). Importantly, tumour escaping other death have been suggested to maintain acquire sensitivity ferroptosis. Therefore, therapeutic exploitation in has received increasing attention. Here, we systematically review current literature on signalling, cross-signalling cellular metabolism potential role for suppression immunology. By summarising findings biology relevant cancer, aim point out new conceptual avenues utilising systemic treatment approaches cancer.

Language: Английский

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Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure

Cell Death and Disease, Journal Year: 2020, Volume and Issue: 11(2)

Published: Feb. 24, 2020

Acetaminophen (APAP) overdose is a common cause of drug-induced acute liver failure. Although hepatocyte cell death considered to be the critical event in APAP-induced hepatotoxicity, underlying mechanism remains unclear. Ferroptosis newly discovered type that caused by loss cellular redox homeostasis. As glutathione (GSH) depletion triggers we investigated role ferroptosis murine model hepatotoxicity (evaluated terms ALT, AST, and histopathological score), lipid peroxidation (4-HNE MDA), upregulation maker PTGS2 mRNA were markedly prevented ferroptosis-specific inhibitor ferrostatin-1 (Fer-1). Fer-1 treatment also completely mortality induced high-dose APAP. Similarly, iron chelator deferoxamine. Using mass spectrometry, found peroxides derived from n-6 fatty acids, mainly arachidonic acid, elevated APAP, auto-oxidation predominant APAP-derived oxidation. was genetic inhibition acyl-CoA synthetase long-chain family member 4 or α-tocopherol supplementation. We responsible for death. Our findings provide new insights into suggest potential therapeutic target

Language: Английский

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The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators

Biomedicine & Pharmacotherapy, Journal Year: 2021, Volume and Issue: 136, P. 111228 - 111228

Published: Jan. 14, 2021

Iron overload is increasingly implicated as a contributor to the pathogenesis of COVID-19. Indeed, several manifestations COVID-19, such inflammation, hypercoagulation, hyperferritinemia, and immune dysfunction are also reminiscent iron overload. Although essential for all living cells, free unbound iron, resulting from dysregulation overload, very reactive potentially toxic due its role in generation oxygen species (ROS). ROS react with damage cellular lipids, nucleic acids, proteins, consequent activation either acute or chronic inflammatory processes multiple clinical conditions. Moreover, iron-catalyzed lipid exerts direct causative effect on newly discovered nonapoptotic cell death known ferroptosis. Unlike apoptosis, ferroptosis immunogenic not only leads amplified but promotes series reactions associated inflammation. chelators generally safe proven protect patients conditions characterized by There an abundance evidence that possess antiviral activities. Furthermore, naturally occurring chelator lactoferrin (Lf) immunomodulatory well anti-inflammatory effects can bind receptors used coronaviruses thereby blocking their entry into host cells. may consequently be high therapeutic value during present COVID-19 pandemic.

Language: Английский

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Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics

Cell Death and Differentiation, Journal Year: 2020, Volume and Issue: 28(5), P. 1644 - 1657

Published: Dec. 17, 2020

Ferroptosis is an iron-dependent form of regulated necrosis associated with lipid peroxidation. Despite its key role in the inflammatory outcome ferroptosis, little known about molecular events leading to disruption plasma membrane during this type cell death. Here we show that a sustained increase cytosolic Ca2+ hallmark ferroptosis precedes complete bursting cell. We report damage nanopores few nanometers radius and but not peroxidation, can be delayed by osmoprotectants. Importantly, fluxes induce activation ESCRT-III-dependent repair machinery, which counterbalances kinetics death modulates immunological signature ferroptosis. Our findings provide unifying concept prior rupture common feature types position ESCRT-III as general protective mechanism these lytic pathways.

Language: Английский

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Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

American Journal of Transplantation, Journal Year: 2020, Volume and Issue: 20(6), P. 1606 - 1618

Published: Jan. 7, 2020

Hepatic ischemia-reperfusion (I/R) injury is a major problem in liver transplantation (LT). Although hepatocyte cell death the initial event hepatic I/R injury, underlying mechanism remains unclear. In present study, we retrospectively analyzed clinical data of 202 pediatric living donor LT and found that high serum ferritin level, marker iron overload, an independent risk factor for damage after LT. Since ferroptosis has been recently discovered as iron-dependent triggered by loss cellular redox homeostasis, investigated role murine model damage, lipid peroxidation, upregulation Ptgs2 were induced I/R, all these manifestations markedly prevented ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or α-tocopherol. Fer-1 also inhibited I/R-induced inflammatory responses. Furthermore, was attenuated chelation deferoxamine exacerbated overload with diet. These findings demonstrate novel LT, contributes to pathogenesis injury.

Language: Английский

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An innovative NRF2 nano-modulator induces lung cancer ferroptosis and elicits an immunostimulatory tumor microenvironment

Theranostics, Journal Year: 2021, Volume and Issue: 11(14), P. 7072 - 7091

Published: Jan. 1, 2021

Simultaneous targeting of both the tumor microenvironment and cancer cells by a single nanomedicine has not been reported to date. Here, we report dual properties zero-valent-iron nanoparticle (ZVI-NP) induce cancer-specific cytotoxicity anti-cancer immunity. Methods: Cancer-specific induced ZVI-NP was determined MTT assay. Mitochondria functional assay, immunofluorescence staining, Western blot, RT-qPCR, ChIP-qPCR assays were used dissect mechanism underlying ZVI-NP-induced ferroptotic cell death. The therapeutic potential evaluated in immunocompetent mice humanized mice. Immune profiles allografts ex vivo cultured immune examined flow cytometry analysis, RT-qPCR immunofluorescence. Results: caused mitochondria dysfunction, intracellular oxidative stress, lipid peroxidation, leading death lung cells. Degradation NRF2 GSK3/β-TrCP through AMPK/mTOR activation enhanced such ferroptosis. In addition, attenuated self-renewal ability downregulated angiogenesis-related genes. Importantly, augmented anti-tumor immunity shifting pro-tumor M2 macrophages M1, decreasing population regulatory T cells, downregulating PD-1 CTLA4 CD8+ potentiate their cytolytic activity against while attenuating PD-L1 expression vitro tumor-bearing particular, ZVI-NPs preferentially accumulated tissues, prominent suppression growth metastasis. Conclusions: This dual-functional established an effective strategy synergistically reprogram immunosuppressive microenvironment, which highlights as advanced integrated strategy.

Language: Английский

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Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance

British Journal of Cancer, Journal Year: 2019, Volume and Issue: 122(2), P. 279 - 292

Published: Dec. 10, 2019

Abstract Background Ferroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. Recent studies have identified small-molecule erastin specifically inhibits transmembrane cystine–glutamate antiporter system x c − , prevents extracellular cystine import ultimately causes ferroptosis in certain cancer In this study, we aimed investigate the molecular mechanism underlying erastin-induced resistance ovarian Methods We treated cells with examined viability, cellular ROS metabolites transsulfuration pathway. also depleted cystathionine β-synthase (CBS) NRF2 CBS dependency erastin-resistant Results found prolonged treatment induced resistance. Upon exposure erastin, gradually adapted deprivation via sustained activation reverse pathway, allowing bypass insult. CBS, biosynthetic enzyme for cysteine, was constantly upregulated critical Knockdown by RNAi caused ferroptotic death, while overexpression conferred determined antioxidant transcriptional factor, constitutively activated transcriptionally CBS. Genetically repression enhanced susceptibility. Conclusions Based on these results, concluded constitutive NRF2/CBS signalling confers This study demonstrates a new resistance, has implications therapeutic response ferroptosis.

Language: Английский

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Mitochondrial quality control in cardiac microvascular ischemia-reperfusion injury: New insights into the mechanisms and therapeutic potentials

Pharmacological Research, Journal Year: 2020, Volume and Issue: 156, P. 104771 - 104771

Published: March 28, 2020

Language: Английский

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