scholarly journals The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope?

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Lihong Mao ◽  
Tianming Zhao ◽  
Yan Song ◽  
Lin Lin ◽  
Xiaofei Fan ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Diseases ◽  
Therapeutic Strategy ◽  
Kidney Injury ◽  
Hepatic Disease ◽  
Therapeutic Concept ◽  
Regulated Cell Death ◽  
Dependent Form ◽  
Molecular Machinery

Abstract Ferroptosis is an iron- and lipotoxicity-dependent form of regulated cell death (RCD). It is morphologically and biochemically distinct from characteristics of other cell death. This modality has been intensively investigated in recent years due to its involvement in a wide array of pathologies, including cancer, neurodegenerative diseases, and acute kidney injury. Dysregulation of ferroptosis has also been linked to various liver diseases and its modification may provide a hopeful and attractive therapeutic concept. Indeed, targeting ferroptosis may prevent the pathophysiological progression of several liver diseases, such as hemochromatosis, nonalcoholic steatohepatitis, and ethanol-induced liver injury. On the contrary, enhancing ferroptosis may promote sorafenib-induced ferroptosis and pave the way for combination therapy in hepatocellular carcinoma. Glutathione peroxidase 4 (GPx4) and system xc− have been identified as key players to mediate ferroptosis pathway. More recently diverse signaling pathways have also been observed. The connection between ferroptosis and other forms of RCD is intricate and compelling, where discoveries in this field advance our understanding of cell survival and fate. In this review, we summarize the central molecular machinery of ferroptosis, describe the role of ferroptosis in non-cancer hepatic disease conditions and discuss the potential to manipulate ferroptosis as a therapeutic strategy.

scholarly journals Ferroptosis in Liver Diseases: An Overview

2020 ◽  
Vol 21 (14) ◽  
pp. 4908 ◽  
Author(s):  
Martina Maria Capelletti ◽  
Hana Manceau ◽  
Hervé Puy ◽  
Katell Peoc’h
Keyword(s):  
Cell Death ◽  
Liver Diseases ◽  
Ischemia Reperfusion Injury ◽  
Primary Liver Cancer ◽  
Ischemia Reperfusion ◽  
Lipid Peroxide ◽  
Kidney Injury ◽  
Redox Active ◽  
Dependent Form ◽  
Repair Activity

Ferroptosis is an iron-dependent form of cell death characterized by intracellular lipid peroxide accumulation and redox imbalance. Ferroptosis shows specific biological and morphological features when compared to the other cell death patterns. The loss of lipid peroxide repair activity by glutathione peroxidase 4 (GPX4), the presence of redox-active iron and the oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids are considered as distinct fingerprints of ferroptosis. Several pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion, p53, Keap1/Nrf2 and phospholipid biosynthesis, can modify susceptibility to ferroptosis. Through the decades, various diseases, including acute kidney injury; cancer; ischemia–reperfusion injury; and cardiovascular, neurodegenerative and hepatic disorders, have been associated with ferroptosis. In this review, we provide a comprehensive analysis of the main biological and biochemical mechanisms of ferroptosis and an overview of chemicals used as inducers and inhibitors. Then, we report the contribution of ferroptosis to the spectrum of liver diseases, acute or chronic. Finally, we discuss the use of ferroptosis as a therapeutic approach against hepatocellular carcinoma, the most common form of primary liver cancer.

scholarly journals The emerging role of ferroptosis in intestinal disease

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Shu Xu ◽  
Yao He ◽  
Lihui Lin ◽  
Peng Chen ◽  
Minhu Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurological Disorders ◽  
Kidney Injury ◽  
Intestinal Disease ◽  
Intestinal Diseases ◽  
Ischaemia Reperfusion ◽  
Regulated Cell Death ◽  
Inflammatory Bowel ◽  
Underlying Mechanisms

AbstractFerroptosis is a newly recognised type of regulated cell death (RCD) characterised by iron-dependent accumulation of lipid peroxidation. It is significantly distinct from other RCDs at the morphological, biochemical, and genetic levels. Recent reports have implicated ferroptosis in multiple diseases, including neurological disorders, kidney injury, liver diseases, and cancer. Ferroptotic cell death has also been associated with dysfunction of the intestinal epithelium, which contributes to several intestinal diseases. Research on ferroptosis may provide a new understanding of intestinal disease pathogenesis that benefits clinical treatment. In this review, we provide an overview of ferroptosis and its underlying mechanisms, then describe its emerging role in intestinal diseases, including intestinal ischaemia/reperfusion (I/R) injury, inflammatory bowel disease (IBD), and colorectal cancer (CRC).

The miR-21 potential of serving as a biomarker for liver diseases in clinical practice

2020 ◽  
Vol 48 (5) ◽  
pp. 2295-2305
Author(s):  
Jiawei Zhang ◽  
Dandan Li ◽  
Rui Zhang ◽  
Peng Gao ◽  
Rongxue Peng ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Liver Diseases ◽  
Hepatic Disease ◽  
Noninvasive Detection ◽  
Diagnosis And Prognosis ◽  
Expected Performance ◽  
Potential Biomarker ◽  
Disease Condition ◽  
Complex Regulatory Network

The role of miR-21 in the pathogenesis of various liver diseases, together with the possibility of detecting microRNA in the circulation, makes miR-21 a potential biomarker for noninvasive detection. In this review, we summarize the potential utility of extracellular miR-21 in the clinical management of hepatic disease patients and compared it with the current clinical practice. MiR-21 shows screening and prognostic value for liver cancer. In liver cirrhosis, miR-21 may serve as a biomarker for the differentiating diagnosis and prognosis. MiR-21 is also a potential biomarker for the severity of hepatitis. We elucidate the disease condition under which miR-21 testing can reach the expected performance. Though miR-21 is a key regulator of liver diseases, microRNAs coordinate with each other in the complex regulatory network. As a result, the performance of miR-21 is better when combined with other microRNAs or classical biomarkers under certain clinical circumstances.

scholarly journals The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4576
Author(s):  
Hung-Yu Lin ◽  
Hui-Wen Ho ◽  
Yen-Hsiang Chang ◽  
Chun-Jui Wei ◽  
Pei-Yi Chu
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Drug Resistant ◽  
Therapeutic Targeting ◽  
The Past ◽  
Regulated Cell Death ◽  
Common Malignancy

Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

scholarly journals Insight into the Double-Edged Role of Ferroptosis in Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1790
Author(s):  
Lei Zhang ◽  
Ruohan Jia ◽  
Huizhen Li ◽  
Huarun Yu ◽  
Keke Ren ◽  
...  
Keyword(s):  
Cell Death ◽  
Digestive System ◽  
Kidney Injury ◽  
Oxygen Species ◽  
Disease Treatment ◽  
The Relationship ◽  
Insight Into ◽  
New Strategies ◽  
Research Hotspots

Ferroptosis, a newly described type of iron-dependent programmed cell death that is distinct from apoptosis, necroptosis, and other types of cell death, is involved in lipid peroxidation (LP), reactive oxygen species (ROS) production, and mitochondrial dysfunction. Accumulating evidence has highlighted vital roles for ferroptosis in multiple diseases, including acute kidney injury, cancer, hepatic fibrosis, Parkinson’s disease, and Alzheimer’s disease. Therefore, ferroptosis has become one of the research hotspots for disease treatment and attracted extensive attention in recent years. This review mainly summarizes the relationship between ferroptosis and various diseases classified by the system, including the urinary system, digestive system, respiratory system, nervous system. In addition, the role and molecular mechanism of multiple inhibitors and inducers for ferroptosis are further elucidated. A deeper understanding of the relationship between ferroptosis and multiple diseases may provide new strategies for researching diseases and drug development based on ferroptosis.

scholarly journals Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Qingfei Chu ◽  
Xinyu Gu ◽  
Qiuxian Zheng ◽  
Jing Wang ◽  
Haihong Zhu
Keyword(s):  
Cell Death ◽  
Liver Cirrhosis ◽  
Liver Disease ◽  
Programmed Cell Death ◽  
Liver Diseases ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Cellular Energetics ◽  
Liver Cell Death

In addition to playing a pivotal role in cellular energetics and biosynthesis, mitochondrial components are key operators in the regulation of cell death. In addition to apoptosis, necrosis is a highly relevant form of programmed liver cell death. Differential activation of specific forms of programmed cell death may not only affect the outcome of liver disease but may also provide new opportunities for therapeutic intervention. This review describes the role of mitochondria in cell death and the mechanism that leads to chronic liver hepatitis and liver cirrhosis. We focus on mitochondrial-driven apoptosis and current knowledge of necroptosis and discuss therapeutic strategies for targeting mitochondrial-mediated cell death in liver diseases.

scholarly journals Autophagy Function and Regulation in Kidney Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 100 ◽  
Author(s):  
Gur P. Kaushal ◽  
Kiran Chandrashekar ◽  
Luis A. Juncos ◽  
Sudhir V. Shah
Keyword(s):  
Cell Death ◽  
Renal Injury ◽  
Mammalian Target Of Rapamycin ◽  
Kidney Injury ◽  
Therapeutic Approaches ◽  
Regulated Necrosis ◽  
Atg Genes ◽  
Cellular Components ◽  
The Impact

Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

scholarly journals Novel insights on targeting ferroptosis in cancer therapy

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Sipeng Zuo ◽  
Jie Yu ◽  
Hui Pan ◽  
Linna Lu
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Cancer Therapy ◽  
Alzheimer Disease ◽  
Cellular Structure ◽  
Redox Balance ◽  
Regulated Cell Death ◽  
Novel Theory ◽  
The Relationship

Abstract Ferroptosis belongs to a novel form of regulated cell death. It is characterized by iron dependence, destruction of intracellular redox balance and non-apoptosis. And cellular structure and molecules level changes also occur abnormally during ferroptosis. It has been proved that ferroptosis exist widespreadly in many diseases, such as heart disease, brain damage or alzheimer disease. At the same time, the role of ferroptosis in cancer cannot be underestimated. More and more indications have told that ferroptosis is becoming a powerful weapon against cancer. In addition, therapies rely on ferroptosis have been applied to the clinic. Therefore, it is necessary to understand this newly discovered form of cell death and its connection with cancer. This review summarizes the mechanism of ferroptosis, ferroptosis inducers based on different targets and inspection methods. At last, we analyzed the relationship between ferroptosis and malignancies, in order to provide a novel theory basis for cancer treatment.

scholarly journals Cell Death in the Kidney

2019 ◽  
Vol 20 (14) ◽  
pp. 3598 ◽  
Author(s):  
Giovanna Priante ◽  
Lisa Gianesello ◽  
Monica Ceol ◽  
Dorella Del Prete ◽  
Franca Anglani
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Apoptotic Cell ◽  
Parenchymal Cell ◽  
Kidney Injury ◽  
Permeability Transition ◽  
Cell Loss ◽  
Relative Contribution ◽  
Regulated Cell Death ◽  
Regulated Necrosis

Apoptotic cell death is usually a response to the cell’s microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury, but does not trigger an inflammatory response. What distinguishes necrosis from apoptosis is the rupture of the plasma membrane, so necrotic cell death is accompanied by the release of unprocessed intracellular content, including cellular organelles, which are highly immunogenic proteins. The relative contribution of apoptosis and necrosis to injury varies, depending on the severity of the insult. Regulated cell death may result from immunologically silent apoptosis or from immunogenic necrosis. Recent advances have enhanced the most revolutionary concept of regulated necrosis. Several modalities of regulated necrosis have been described, such as necroptosis, ferroptosis, pyroptosis, and mitochondrial permeability transition-dependent regulated necrosis. We review the different modalities of apoptosis, necrosis, and regulated necrosis in kidney injury, focusing particularly on evidence implicating cell death in ectopic renal calcification. We also review the evidence for the role of cell death in kidney injury, which may pave the way for new therapeutic opportunities.

scholarly journals Excessive phospholipid peroxidation distinguishes ferroptosis from other cell death modes including pyroptosis

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Bartosz Wiernicki ◽  
Hanne Dubois ◽  
Yulia Y. Tyurina ◽  
Behrouz Hassannia ◽  
Hülya Bayir ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
The Other ◽  
Strong Increase ◽  
Oxygen Species ◽  
Membrane Rupture ◽  
Regulated Cell Death ◽  
Phospholipid Peroxidation ◽  
Differential Involvement

Abstract Lipid peroxidation (LPO) drives ferroptosis execution. However, LPO has been shown to contribute also to other modes of regulated cell death (RCD). To clarify the role of LPO in different modes of RCD, we studied in a comprehensive approach the differential involvement of reactive oxygen species (ROS), phospholipid peroxidation products, and lipid ROS flux in the major prototype modes of RCD viz. apoptosis, necroptosis, ferroptosis, and pyroptosis. LC-MS oxidative lipidomics revealed robust peroxidation of three classes of phospholipids during ferroptosis with quantitative predominance of phosphatidylethanolamine species. Incomparably lower amounts of phospholipid peroxidation products were found in any of the other modes of RCD. Nonetheless, a strong increase in lipid ROS levels was detected in non-canonical pyroptosis, but only during cell membrane rupture. In contrast to ferroptosis, lipid ROS apparently was not involved in non-canonical pyroptosis execution nor in the release of IL-1β and IL-18, while clear dependency on CASP11 and GSDMD was observed. Our data demonstrate that ferroptosis is the only mode of RCD that depends on excessive phospholipid peroxidation for its cytotoxicity. In addition, our results also highlight the importance of performing kinetics and using different methods to monitor the occurrence of LPO. This should open the discussion on the implication of particular LPO events in relation to different modes of RCD.

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