Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Feb. 23, 2022

Abstract Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available remove clot, and mechanism of neuronal death during ischemic is still in debate. Ferroptosis increasingly appreciated as cell after ischemia various organs. Here we report that serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization subsequent esterification gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin ACSL4 genes/proteins, their pro-ferroptotic phosphatidylethanolamine lipid products, prominently altered upon middle cerebral artery occlusion rodents. Genetically or pharmacologically inhibiting multiple points this pathway attenuated outcomes models vitro vivo. Therefore, thrombin-ACSL4 axis may be key therapeutic target ameliorate injury stroke.

Language: Английский

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NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron–Sulfur Cluster Proteins

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(9), P. 2180 - 2197

Published: June 30, 2022

Pancreatic ductal adenocarcinomas (PDAC) depend on autophagy for survival; however, the metabolic substrates that provides to drive PDAC progression are unclear. Ferritin, cellular iron storage complex, is targeted lysosomal degradation (ferritinophagy) by selective adaptor NCOA4, resulting in release of utilization. Using patient-derived and murine models PDAC, we demonstrate ferritinophagy upregulated sustain availability, thereby promoting tumor progression. Quantitative proteomics reveals fuels iron-sulfur cluster protein synthesis support mitochondrial homeostasis. Targeting NCOA4 leads growth delay prolonged survival but with development compensatory acquisition pathways. Finally, enhanced accelerates tumorigenesis, an elevated expression signature predicts poor prognosis patients PDAC. Together, our data reveal maintenance homeostasis a critical function autophagy, define NCOA4-mediated as therapeutic target Autophagy metabolism dependencies However, therapies these pathways lacking. We identify ferritin ("ferritinophagy") Ferritinophagy supports represents new See related commentary Jain Amaravadi, p. 2023. article Ravichandran et al., 2198. This highlighted In Issue feature, 2007.

Language: Английский

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Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 10, 2023

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other modes, plays pivotal role in regulating tumorigenesis offers new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications posttranslational (PTMs) promote resistance, cancer progression, metastasis. Accumulating studies indicate that can transcriptionally translationally determine vulnerability to ferroptosis functions as driver nervous system diseases (NSDs), cardiovascular (CVDs), liver diseases, lung kidney diseases. In this review, we first summarize the core molecular mechanisms ferroptosis. Then, roles processes, including histone PTMs, DNA methylation, noncoding RNA regulation such phosphorylation, ubiquitination, SUMOylation, acetylation, ADP-ribosylation, are concisely discussed. The PTMs genesis cancers, NSD, CVDs, well application PTM modulators therapy these then discussed detail. Elucidating mediated by will facilitate development promising combination therapeutic regimens containing or PTM-targeting agents inducers be used overcome chemotherapeutic resistance could prevent addition, highlight potential approaches chemoresistance halt

Language: Английский

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Iron, ferroptosis, and ischemic stroke

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 165(4), P. 487 - 520

Published: March 13, 2023

Abstract Over 30 million people suffer from the consequences of ischemic stroke. The precise molecular mechanism neuronal damage during stroke remains unclear; therefore, effective treatment post‐ischemic a critical challenge. Recently, iron has emerged as crucial factor in post‐reperfusion injuries, participating cell peroxidation, excitotoxicity, and distinctive death pathway, namely, ferroptosis. Since is tightly regulated brain important for functions, imbalance its metabolism, including overload deficiency, been shown to impact outcomes. This review summarizes current understanding pathological events associated with discusses relevant drug development. image

Language: Английский

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The mechanism of ferroptosis and its related diseases

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Oct. 16, 2023

Abstract Ferroptosis, a regulated form of cellular death characterized by the iron-mediated accumulation lipid peroxides, provides novel avenue for delving into intersection metabolism, oxidative stress, and disease pathology. We have witnessed mounting fascination with ferroptosis, attributed to its pivotal roles across diverse physiological pathological conditions including developmental processes, metabolic dynamics, oncogenic pathways, neurodegenerative cascades, traumatic tissue injuries. By unraveling intricate underpinnings molecular machinery, contributors, signaling conduits, regulatory networks governing researchers aim bridge gap between intricacies this unique mode multifaceted implications health disease. In light rapidly advancing landscape ferroptosis research, we present comprehensive review aiming at extensive in origins progress human diseases. This concludes careful analysis potential treatment approaches carefully designed either inhibit or promote ferroptosis. Additionally, succinctly summarized therapeutic targets compounds that hold promise targeting within various facet underscores burgeoning possibilities manipulating as strategy. summary, enriched insights both investigators practitioners, while fostering an elevated comprehension latent translational utilities. revealing basic processes investigating possibilities, crucial resource scientists medical aiding deep understanding effects situations.

Language: Английский

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Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 14, 2024

Iron, an essential mineral in the body, is involved numerous physiological processes, making maintenance of iron homeostasis crucial for overall health. Both overload and deficiency can cause various disorders human diseases. Ferroptosis, a form cell death dependent on iron, characterized by extensive peroxidation lipids. Unlike other kinds classical unprogrammed death, ferroptosis primarily linked to disruptions metabolism, lipid peroxidation, antioxidant system imbalance. Ferroptosis regulated through transcription, translation, post-translational modifications, which affect cellular sensitivity ferroptosis. Over past decade or so, diseases have been as part their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous cardiovascular musculoskeletal Ferroptosis-related proteins become attractive targets many major that are currently incurable, some regulators shown therapeutic effects clinical trials although further validation potential needed. Therefore, in-depth analysis its molecular mechanisms may offer additional strategies prevention treatment. In this review, we discuss significance contribution etiology development along with evidence supporting targeting approach. Importantly, evaluate recent promising interventions, providing guidance future targeted treatment therapies against

Language: Английский

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Iron homeostasis imbalance and ferroptosis in brain diseases

MedComm, Journal Year: 2023, Volume and Issue: 4(4)

Published: June 26, 2023

Brain iron homeostasis is maintained through the normal function of blood-brain barrier and regulation at systemic cellular levels, which fundamental to brain function. Excess can catalyze generation free radicals Fenton reactions due its dual redox state, thus causing oxidative stress. Numerous evidence has indicated diseases, especially stroke neurodegenerative are closely related mechanism imbalance in brain. For one thing, diseases promote accumulation. another, accumulation amplifies damage nervous system exacerbates patients' outcomes. In addition, triggers ferroptosis, a newly discovered iron-dependent type programmed cell death, neurodegeneration received wide attention recent years. this context, we outline metabolism focus on current stroke, Alzheimer's disease, Parkinson's disease. Meanwhile, also discuss ferroptosis simultaneously enumerate drugs for chelators inhibitors.

Language: Английский

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In defence of ferroptosis

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 2, 2025

Abstract Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained cellular defences. Ferroptosis increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation conceived to occur not an endogenous executioner, but withdrawal guardians that otherwise constantly oppose induction. Here, we profile key ferroptotic defence strategies including regulation, modulation enzymes metabolite systems: glutathione reductase (GR), suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase (NQO1), Dihydrofolate (DHFR), retinal reductases dehydrogenases (RDH) thioredoxin (TR). A common thread uniting all metabolites combat lipid during dependence on reductant, nicotinamide adenine dinucleotide phosphate (NADPH). We will outline how cells control central carbon metabolism produce NADPH necessary precursors defend against ferroptosis. Subsequently discuss evidence for dysregulation different disease contexts glucose-6-phosphate dehydrogenase deficiency, cancer neurodegeneration. Finally, several anti-ferroptosis therapeutic spanning use radical trapping agents, dependent redox support highlight current landscape clinical trials focusing

Language: Английский

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O-GlcNAcylation attenuates ischemia-reperfusion-induced pulmonary epithelial cell ferroptosis via the Nrf2/G6PDH pathway

BMC Biology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 4, 2025

Lung ischemia–reperfusion (I/R) injury is a common clinical pathology associated with high mortality. The pathophysiology of lung I/R involves ferroptosis and elevated protein O-GlcNAcylation levels, while the effect on remains unclear. This research aimed to explore reducing in pulmonary epithelial cells caused by I/R. First, we identified O-GlcNAc transferase 1 (Ogt1) as differentially expressed gene acute injury/acute respiratory distress syndrome (ALI/ARDS) patients, using single-cell sequencing, Gene Ontology analysis (GO analysis) revealed enrichment process. We found time-dependent dynamic alteration during injury. Proteomics proteins enriched multiple redox-related pathways based KEGG annotation. Thus, generated Ogt1-conditional knockout mice that Ogt1 deficiency aggravated ferroptosis, evidenced lipid reactive oxygen species (lipid ROS), malondialdehyde (MDA), Fe2+, well alterations critical expression glutathione peroxidase 4 (GPX4) solute carrier family 7 member 11 (SLC7A11). Consistently, inhibited sensitivity hypoxia/reoxygenation (H/R) injury-induced TC-1 via O-GlcNAcylated NF-E2-related factor-2 (Nrf2). Furthermore, both chromatin immunoprecipitation (ChIP) assay dual-luciferase reporter indicated Nrf2 could bind translation start site (TSS) glucose-6-phosphate dehydrogenase (G6PDH) promote its transcriptional activity. As an important rate-limiting enzyme pentose phosphate pathway (PPP), G6PDH provided mass nicotinamide adenine dinucleotide (NADPH) improve redox state (GSH) eventually led resistance. Rescue experiments proved knockdown or Nrf2-T334A (O-GlcNAcylation site) mutation abolished protective In summary, protect against Nrf2/G6PDH pathway. Our work will provide new basis for therapeutic strategies ischemia–reperfusion-induced

Language: Английский

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Targeting Ferroptosis as a Promising Therapeutic Strategy for Ischemia-Reperfusion Injury

Antioxidants, Journal Year: 2022, Volume and Issue: 11(11), P. 2196 - 2196

Published: Nov. 6, 2022

Ischemia-reperfusion (I/R) injury is a major challenge in perioperative medicine that contributes to pathological damage various conditions, including ischemic stroke, myocardial infarction, acute lung injury, liver transplantation, kidney and hemorrhagic shock. I/R often irreversible, current treatments for are limited. Ferroptosis, type of regulated cell death characterized by the iron-dependent accumulation lipid hydroperoxides, has been implicated multiple diseases, injury. Emerging evidence suggests ferroptosis can serve as therapeutic target alleviate pharmacological strategies targeting have developed models. Here, we systematically summarize recent advances research on provide comprehensive analysis ferroptosis-regulated genes investigated context I/R, well applications regulators, insights into developing this devastating disease.

Language: Английский

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