Ferroptosis in liver disease: new insights into disease mechanisms

Cell Death Discovery, Journal Year: 2021, Volume and Issue: 7(1)

Published: Oct. 5, 2021

Abstract Characterized by excessive iron accumulation and lipid peroxidation, ferroptosis is a novel form of iron-dependent cell death, which morphologically, genetically, biochemically distinct from other well-known death. In recent years, has been quickly gaining attention in the field liver diseases, as predisposed to oxidative injury generally, primary characteristic most major diseases. current review, we first delineate three cellular defense mechanisms against (GPx4 mitochondria cytosol, FSP1 on plasma membrane, DHODH mitochondria), along with four canonical modulators (system Xc − , nuclear factor erythroid 2-related 2, p53, GTP cyclohydrolase-1). Next, review progress studies delineating molecular underlying pathophysiology several common diseases including ischemia/reperfusion-related (IRI), nonalcoholic fatty disease (NAFLD), alcoholic (ALD), hemochromatosis (HH), drug-induced (DILI), hepatocellular carcinoma (HCC). Furthermore, also highlight both challenges promises that emerged should be addressed pursued future investigations before regulation could adopted an effective therapeutic target clinical practice.

Language: Английский

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The gut microbiota metabolite capsiate promotes Gpx4 expression by activating TRPV1 to inhibit intestinal ischemia reperfusion-induced ferroptosis

Gut Microbes, Journal Year: 2021, Volume and Issue: 13(1)

Published: Jan. 1, 2021

Ferroptosis, a new type of cell death has been found to aggravate intestinal ischemia/reperfusion (I/R) injury. However, little is known about the changes gut microbiota and metabolites in I/R role on ferroptosis-induced This study aimed establish mouse model ileum organoid hypoxia/reoxygenation (H/R) explore during protective ability capsiate (CAT) against ferroptosis-dependent Intestinal induced disturbance significant metabolites. We that CAT metabolite levels preoperative stool patients undergoing cardiopulmonary bypass were negatively correlated with Furthermore, reduced injury vivo vitro. effects abolished by RSL3, an inhibitor glutathione peroxidase 4 (Gpx4), which negative regulator ferroptosis. also promote Gpx4 expression inhibit was abrogated JNJ-17203212, antagonist transient receptor potential cation channel subfamily V member 1 (TRPV1). suggests enhances inhibits ferroptosis activating TRPV1 injury, providing avenue for management

Language: Английский

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The critical role and molecular mechanisms of ferroptosis in antioxidant systems: a narrative review

Annals of Translational Medicine, Journal Year: 2022, Volume and Issue: 10(6), P. 368 - 368

Published: March 1, 2022

Background and Objective: Ferroptosis is a recently discovered form of cell death which differs from other forms in terms morphology, biochemistry, regulatory mechanisms. regulated by complex system the precise molecular mechanisms are still being elucidated. Over past few years, extensive research has revealed that essence ferroptosis iron-dependent accumulation lipid hydroperoxides induced oxidative stress, System Xc-glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway main prevention system. Meanwhile, antioxidant systems have also been implicated regulating ferroptosis, including transsulfuration pathway, mevalonate inhibitory protein 1 (FSP1)-Coenzyme Q10 (CoQ10) dihydroorotate dehydrogenase (DHODH)-dihydroubiquione (CoQH2) GTP cyclohydrolase-1 (GCH1)-tetrahydrobiopterin (BH4) pathway. This article reviews its critical role systems, aiming to reveal antioxidation an important method inhibiting provide new direction for treatment ferroptosis-related diseases. Methods: We searched all original papers about using PubMed November 2021. The search used included: ‘ferroptosis’, ‘ferroptosis inducers’, inhibitors’, GSH’, GPX4’, Xc-’, ‘SLC7A11’, ‘P53’, ‘NRF2 ferroptosis’, ‘iron metabolism’, ‘lipid peroxidation’, ‘antioxidant systems’, ‘transsulfuration pathway’, ‘mevalonate ‘FSP1-CoQ10’, ‘DHODH-CoQH2’, ‘GCH1-BH4’. Key Content Findings: first introduced origin common inhibitors inducers. Next, we discussed existing studies. Finally, briefly summarized relationship between It reveals ferroptosis. Conclusions: review discusses recent rapid progress understanding several systems.

Language: Английский

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Iron Overload, Oxidative Stress, and Ferroptosis in the Failing Heart and Liver

Antioxidants, Journal Year: 2021, Volume and Issue: 10(12), P. 1864 - 1864

Published: Nov. 24, 2021

Iron accumulation is a key mediator of several cytotoxic mechanisms leading to the impairment redox homeostasis and cellular death. overload often associated with haematological diseases which require regular blood transfusion/phlebotomy, it represents common complication in thalassaemic patients. Major damages predominantly occur liver heart, specific form cell death recently named ferroptosis. Different from apoptosis, necrosis, autophagy, ferroptosis strictly dependent on iron reactive oxygen species, dysregulation mitochondrial structure/function. Susceptibility intracellular antioxidant capacity varies according different types. Chemotherapy-induced cardiotoxicity has been proven be mediated by ferroptosis, whereas there evidence about role ferritin protecting cardiomyocytes consequent heart failure. Another paradigmatic organ for transfusion-associated due liver, yet elucidated. Some studies report initiation hepatic inflammation processes while others provide an involvement pathologies including immune-related hepatitis acute In this manuscript, we aim review literature address putative features between response liver. A better comprehension (dys)similarities pivotal development future therapeutic strategies that can designed specifically target type attempt minimize iron-overload effects organs.

Language: Английский

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Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects

Free Radical Biology and Medicine, Journal Year: 2021, Volume and Issue: 165, P. 229 - 242

Published: Jan. 26, 2021

Language: Английский

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Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis

Acta Pharmacologica Sinica, Journal Year: 2022, Volume and Issue: 44(5), P. 1014 - 1028

Published: Nov. 2, 2022

Language: Английский

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Targeting Mitochondrial ROS-Mediated Ferroptosis by Quercetin Alleviates High-Fat Diet-Induced Hepatic Lipotoxicity

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: April 12, 2022

Background: The protective effect of quercetin on nonalcoholic fatty liver disease (NAFLD) has been reported, but its mechanism remains poorly understood. Recently, was reported to be capable inhibiting ferroptosis, which is a recognized type regulated cell death. Moreover, hepatic ferroptosis plays an important role in the progression NAFLD, experimental evidence limited. Hence, our study aimed investigate high-fat diet (HFD)-induced NAFLD and further elucidate underlying molecular mechanism. Methods: C57BL/6J mice were fed either normal (ND), HFD, or HFD supplemented with for 12 weeks. Hepatic lipid peroxidation, steatosis, iron overload examined. In vitro, steatotic L-02 cells used potential Results: We found that caused accumulation liver, rescued by supplementation. Consistent vivo results, alleviated droplet reduced levels reactive oxygen species (ROS) cells. Using mitochondrial ROS (MtROS) scavenger (Mito-TEMPO) specific inhibitor (Fer-1), we remarkably peroxidation reducing MtROS-mediated Conclusion: Our data showed consumption induced triggered ultimately leading lipotoxicity, can quercetin. Findings from this provide new insight into prevention treatment NAFLD.

Language: Английский

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FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner

Journal of Advanced Research, Journal Year: 2023, Volume and Issue: 55, P. 45 - 60

Published: Feb. 23, 2023

Liver fibrosis is a life-threatening pathological anomaly which usually evolves into advanced liver cirrhosis and hepatocellular carcinoma although limited therapeutic option readily available. FUN14 domain containing 1 (FUNDC1) mitophagy receptor with little information in fibrosis. This study was designed to examine the role for FUNDC1 carbon tetrachloride (CCl4)-induced injury. GEO database analysis subsequent validation of biological processes including western blot, immunofluorescence, co-immunoprecipitation were applied clarify regulatory on ferroptosis. Our data revealed elevated levels tissues patients fibrotic injury CCl4-challenged mice. deletion protected against CCl4-induced hepatic anomalies Moreover, ameliorated ferroptosis vivo vitro. Mechanically, interacted glutathione peroxidase (GPx4), selenoenzyme neutralize lipid hydroperoxides ferroptosis, via its 96–133 amino acid facilitate GPx4 recruitment mitochondria from cytoplasm. entered through mitochondrial protein import system-the translocase outer membrane/translocase inner membrane (TOM/TIM) complex, prior degradation mainly along ROS-induced damaged mitochondria, resulting hepatocyte Taken together, our favored that promoted binding translocation TOM/TIM where degraded by trigger Targeting may be promising approach

Language: Английский

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An overview of ferroptosis in non-alcoholic fatty liver disease

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 153, P. 113374 - 113374

Published: July 11, 2022

Non-alcoholic fatty liver disease (NAFLD) is a public health problem associated with high mortality and morbidity rates worldwide. Presently, its complex pathophysiology still unclear, there no specific drug to reverse NAFLD. Ferroptosis an iron-dependent non-apoptotic form of cell death characterized by the iron-induced accumulation lipid reactive oxygen species (ROS), which damage nucleic acids, proteins, lipids; generate intracellular oxidative stress; ultimately cause death. Emerging evidence indicates that ferroptosis involved in progression NAFLD, although mechanism action NAFLD poorly understood. Herein, we summarize certain diseases, especially pathogenesis discuss potential therapeutic approaches currently used treat This review also highlights further directions for treatment prevention related diseases.

Language: Английский

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Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 8, 2023

Dietary methionine interventions are beneficial to apoptosis-inducing chemotherapy and radiotherapy for cancer, while their effects on ferroptosis-targeting therapy immunotherapy unknown. Here we show the length of time deprivation affects tumoral ferroptosis differently. Prolonged prevents glutathione (GSH) depletion from exceeding death threshold by blocking cation transport regulator homolog 1 (CHAC1) protein synthesis. Whereas, short-term starvation accelerates stimulating CHAC1 transcription. In vivo, dietary with intermittent but not sustained augments ferroptosis. Intermittent also sensitizes tumor cells against CD8+ T cell-mediated cytotoxicity synergize checkpoint blockade upregulation. Clinically, correlates clinical benefits improved survival in cancer patients treated blockades. Lastly, triple combination deprivation, system xc- inhibitor PD-1 shows superior antitumor efficacy. Thus, is a promising regimen target augment immunotherapy.

Language: Английский

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