-
Nature Reviews. Molecular Cell Biology Apr 2021The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by... (Review)
Review
The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.
Topics: Animals; Ferroptosis; Gene Regulatory Networks; Humans; Lipid Peroxidation; Neoplasms; Oxidation-Reduction; Reproducibility of Results
PubMed: 33495651
DOI: 10.1038/s41580-020-00324-8 -
Cell Research Feb 2021Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has... (Review)
Review
Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.
Topics: Animals; Antioxidants; Autophagy; Epigenesis, Genetic; Ferroptosis; Humans; Iron; Lipid Peroxidation; NF-E2-Related Factor 2; Neoplasms; Reactive Oxygen Species; Signal Transduction
PubMed: 33268902
DOI: 10.1038/s41422-020-00441-1 -
Cell Death & Disease Feb 2020Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation... (Review)
Review
Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases.
Topics: Acute Kidney Injury; Antioxidants; Cell Death; Ferroptosis; Iron; Lipid Metabolism; Lipid Peroxidation; Neoplasms; Nervous System Diseases; Reperfusion Injury
PubMed: 32015325
DOI: 10.1038/s41419-020-2298-2 -
Signal Transduction and Targeted Therapy Jun 2022In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many... (Review)
Review
In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not to ICIs, partly caused by the absence of tumor-infiltrating lymphocytes (TILs), significantly limits the application of ICIs. Converting these immune "cold" tumors into "hot" tumors that may respond to ICIs is an unsolved question in cancer immunotherapy. Since it is a general characteristic of cancers to resist apoptosis, induction of non-apoptotic regulated cell death (RCD) is emerging as a new cancer treatment strategy. Recently, several studies have revealed the interaction between non-apoptotic RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, and necroptosis exhibit synergistic antitumor immune responses while possibly exerting inhibitory effects on antitumor immune responses. Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs. This review summarizes the multilevel relationship between antitumor immunity and non-apoptotic RCD, including autophagy, ferroptosis, pyroptosis, and necroptosis, and the potential targeting application of non-apoptotic RCD to improve the efficacy of immunotherapy in malignancy.
Topics: Autophagy; Ferroptosis; Humans; Immunologic Factors; Immunotherapy; Necroptosis; Neoplasms; Pyroptosis
PubMed: 35725836
DOI: 10.1038/s41392-022-01046-3 -
Molecular Cell Jun 2022Ferroptosis, a newly emerged form of regulated necrotic cell death, has been demonstrated to play an important role in multiple diseases including cancer,... (Review)
Review
Ferroptosis, a newly emerged form of regulated necrotic cell death, has been demonstrated to play an important role in multiple diseases including cancer, neurodegeneration, and ischemic organ injury. Mounting evidence also suggests its potential physiological function in tumor suppression and immunity. The execution of ferroptosis is driven by iron-dependent phospholipid peroxidation. As such, the metabolism of biological lipids regulates ferroptosis via controlling phospholipid peroxidation, as well as various other cellular processes relevant to phospholipid peroxidation. In this review, we provide a comprehensive analysis by focusing on how lipid metabolism impacts the initiation, propagation, and termination of phospholipid peroxidation; how multiple signal transduction pathways communicate with ferroptosis via modulating lipid metabolism; and how such intimate cross talk of ferroptosis with lipid metabolism and related signaling pathways can be exploited for the development of rational therapeutic strategies.
Topics: Ferroptosis; Iron; Lipid Metabolism; Lipid Peroxidation; Phospholipids
PubMed: 35390277
DOI: 10.1016/j.molcel.2022.03.022 -
Oncogene Jan 2023Metastasis is an important factor contributing to poor prognosis in patients with gastric cancer; yet, the molecular mechanism leading to this cell behavior is still not...
Metastasis is an important factor contributing to poor prognosis in patients with gastric cancer; yet, the molecular mechanism leading to this cell behavior is still not well understood. In this study, we explored the role of cysteine protease inhibitor SN (Cystatin SN, CST1) in promoting gastric cancer metastasis. We hypothesized that CST1 could regulate gastric cancer progression by regulating GPX4 and ferroptosis. Whole transcriptome sequencing suggested that the expression of CST1 was significantly increased in metastatic cancer, and high CST1 expression was correlated with a worse prognosis. Our data further confirmed that the overexpression of CST1 may significantly promote the migration and invasion of gastric cancer cells in vitro and enhance liver, lung, and peritoneal metastasis of gastric cancer in nude mice. Meanwhile, high expression of CST1 promoted the epithelial-mesenchymal transition (EMT) of gastric cancer cells. Mechanistically, a co-immunoprecipitation experiment combined with mass spectrometry analysis confirmed that CST1 could interact with GPX4, a key protein regulating ferroptosis. CST1 relieves GPX4 ubiquitination modification by recruiting OTUB1, improving GPX4 protein stability and reducing intracellular reactive oxygen species (ROS), thereby inhibiting ferroptosis and, in turn, promoting gastric cancer metastasis. Moreover, clinical data suggested that CST1 is significantly increased in peripheral blood and ascites of gastric cancer patients with metastasis; multivariate Cox regression model analysis showed that CST1 was an independent risk factor for the prognosis of gastric cancer patients. Overall, our results elucidated a critical pathway through which high CST1 expression protects gastric cancer cells from undergoing ferroptosis, thus promoting its progression and metastasis. CST1 may be used as a new oncological marker and potential therapeutic target for gastric cancer metastasis.
Topics: Animals; Mice; Cell Line, Tumor; Salivary Cystatins; Stomach Neoplasms; Mice, Nude; Ferroptosis
PubMed: 36369321
DOI: 10.1038/s41388-022-02537-x -
Journal of Hematology & Oncology Mar 2019Ferroptosis is a novel type of cell death with distinct properties and recognizing functions involved in physical conditions or various diseases including cancers. The... (Review)
Review
Ferroptosis is a novel type of cell death with distinct properties and recognizing functions involved in physical conditions or various diseases including cancers. The fast-growing studies of ferroptosis in cancer have boosted a perspective for its usage in cancer therapeutics. Here, we review the current findings of ferroptosis regulation and especially focus on the function of ncRNAs in mediating the process of cell ferroptotic death and on how ferroptosis was in relation to other regulated cell deaths. Aberrant ferroptosis in diverse cancer types and tissues were summarized, and we elaborated recent data about the novel actors of some "conventional" drugs or natural compounds as ferroptosis inducers in cancer. Finally, we deliberate future orientation for ferroptosis in cancer cells and current unsettled issues, which may forward the speed of clinical use of ferroptosis induction in cancer treatment.
Topics: Cell Death; Ferroptosis; Humans; Neoplasms
PubMed: 30925886
DOI: 10.1186/s13045-019-0720-y -
The FEBS Journal Nov 2022As a type of lytic cell death driven by unrestricted lipid peroxidation and subsequent plasma membrane damage, ferroptosis occurs and develops because of sophisticated... (Review)
Review
As a type of lytic cell death driven by unrestricted lipid peroxidation and subsequent plasma membrane damage, ferroptosis occurs and develops because of sophisticated signals and regulatory mechanisms. The reactive oxygen species (ROS) used to initiate ferroptosis come from a variety of sources, including iron-mediated Fenton reactions, mitochondrial ROS, and membrane-associated ROS driven by the NOX protein family. Polyunsaturated fatty acid-containing phospholipids are the main substrates of lipid peroxidation in ferroptosis, which is positively regulated by enzymes, such as ACSL4, LPCAT3, ALOXs, or POR. Selective activation of autophagic degradation pathways promotes ferroptosis by increasing iron accumulation to cause lipid peroxidation. In contrast, system xc -glutathione-GPX4 axis plays a central role in limiting lipid peroxidation, although other antioxidants (such as coenzyme Q10 and tetrahydrobiopterin) can also inhibit ferroptosis. A main nuclear mechanism of cell defense against ferroptosis is the activation of the NFE2L2-dependent antioxidant response by transcriptionally upregulating the expression of antioxidants or cytoprotective genes. Additionally, the membrane damage caused by ferroptotic stimulus can be repaired by ESCRT-III-dependent membrane scission machinery. In this review, we summarize recent progress in understanding the signaling pathways and defense mechanisms of ferroptosis.
Topics: Ferroptosis; Reactive Oxygen Species; Antioxidants; Signal Transduction; Iron; Defense Mechanisms
PubMed: 34092035
DOI: 10.1111/febs.16059 -
Cell Metabolism Jan 2023Treatment of triple-negative breast cancer (TNBC) remains challenging. Deciphering the orchestration of metabolic pathways in regulating ferroptosis will provide new...
Treatment of triple-negative breast cancer (TNBC) remains challenging. Deciphering the orchestration of metabolic pathways in regulating ferroptosis will provide new insights into TNBC therapeutic strategies. Here, we integrated the multiomics data of our large TNBC cohort (n = 465) to develop the ferroptosis atlas. We discovered that TNBCs had heterogeneous phenotypes in ferroptosis-related metabolites and metabolic pathways. The luminal androgen receptor (LAR) subtype of TNBC was characterized by the upregulation of oxidized phosphatidylethanolamines and glutathione metabolism (especially GPX4), which allowed the utilization of GPX4 inhibitors to induce ferroptosis. Furthermore, we verified that GPX4 inhibition not only induced tumor ferroptosis but also enhanced antitumor immunity. The combination of GPX4 inhibitors and anti-PD1 possessed greater therapeutic efficacy than monotherapy. Clinically, higher GPX4 expression correlated with lower cytolytic scores and worse prognosis in immunotherapy cohorts. Collectively, this study demonstrated the ferroptosis landscape of TNBC and revealed an innovative immunotherapy combination strategy for refractory LAR tumors.
Topics: Humans; Ferroptosis; Immunotherapy; Triple Negative Breast Neoplasms
PubMed: 36257316
DOI: 10.1016/j.cmet.2022.09.021 -
The Journal of Experimental Medicine Jun 2021Ferroptosis is a type of regulated necrosis that is triggered by a combination of iron toxicity, lipid peroxidation, and plasma membrane damage. The upstream inducers of... (Review)
Review
Ferroptosis is a type of regulated necrosis that is triggered by a combination of iron toxicity, lipid peroxidation, and plasma membrane damage. The upstream inducers of ferroptosis can be divided into two categories (biological versus chemical) and activate two major pathways (the extrinsic/transporter versus the intrinsic/enzymatic pathways). Excessive or deficient ferroptotic cell death is implicated in a growing list of physiological and pathophysiological processes, coupled to a dysregulated immune response. This review focuses on new discoveries related to how ferroptotic cells and their spilled contents shape innate and adaptive immunity in health and disease. Understanding the immunological characteristics and activity of ferroptotic death not only illuminates an intersection between cell death and immunity but may also lead to the development of novel treatment approaches for immunopathological diseases.
Topics: Animals; Ferroptosis; Humans; Immunity; Infections; Inflammation; Lipid Peroxidation
PubMed: 33978684
DOI: 10.1084/jem.20210518