Novel Mechanisms and Therapeutic Opportunities of Ferroptosis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Microenvironment".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 44515

Special Issue Editors

Institute for Cancer Genetics, Herbert Irving Cancer Research Center, College of Physicians & Surgeons, Columbia University, New York, NY 10027, USA
Interests: ferroptosis; cancer
Columbia University Medical Center, New York, NY 10027, USA
Interests: ferroptosis; cancer
Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
Interests: ferroptosis; cancer
The Marine Biomedical Research Institute of Guangdong Zhanjiang, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang 524023, China
Interests: cell death modes (ferroptosis, pyroptosis, necroptosis) mechanisms and targeted drug discovery
Synaptic Transmission Section, National Institute of Neurological Disorders and Stroke, NIH Building 35, Room 2B1010, 35 Convent Drive, Bethesda, MD 20892, USA
Interests: Alzheimer’s disease; neuroinflammation; B-lymphocyte; T-lymphocyte; aging; tumor
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Special Issue Information

Dear Colleagues,

Ferroptosis is a newly identified regulated cell death modality with unique characteristics compared to apoptosis and other types of cell death. Ferroptosis is caused by the disruption of several key metabolic pathways (including the ROS, amino acid, and lipid metabolism pathways) in the cell and is dependent on iron. There are three basic elements for ferroptosis: the substrate of lipid peroxidation, the executor of lipid peroxidation, and the anti-ferroptosis system.

The past decade witnessed the rapid progress in ferroptosis research, both in terms of its molecular mechanism and disease relevance. Classical models of ferroptosis highlight the central role of ACSL4 in the synthesis of the lipid peroxidation substrate, ALOXs as executors of lipid peroxidation, and GPX4 for ferroptosis suppression. Ferroptosis has been demonstrated to be involved in normal development and diverse disorders, including ischemic organ injuries, neurodegenerative diseases, immune system activities, and tumors. The pathological relevance of ferroptosis provides new therapeutic opportunities for these diseases.

As research on ferroptosis goes deeper, novel mechanisms of ferroptosis that are beyond the classical model are emerging. For example, p53-mediated ferroptosis has been proven to be as much of a distinct pathway as GPX4-centered ferroptosis. More and more regulators of ferroptosis are being identified. In addition, ferroptosis exhibits many more roles than expected in the initiation and development of various diseases. More efforts should be made to determine the novel mechanisms and therapeutic opportunities of ferroptosis.

This Special Issue aims to collect papers about how ferroptosis is regulated and how ferroptosis pathways can be targeted to treat diverse diseases. We welcome papers about novel/non-canonical ferroptosis pathways and new drugs therapeutic methods targeting ferroptosis.

Original research articles, reviews, and mini-reviews are welcome in this collection. Topics of interest include but are not limited to the follow:

  1. Novel mechanisms and regulators of ferroptosis;
  2. The role of p53 in both canonical and non-canonical ferroptosis regulation;
  3. Targeting ferroptosis for the treatment of various diseases.

Please note that the findings based on bioinformatic data mining should be validated by experiments.

Dr. Yanqing Liu
Dr. Zhenyi Su
Prof. Dr. Chaoyun Pan
Prof. Dr. Lianxiang Luo
Dr. Xin Wang
Guest Editors

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Keywords

  • ferroptosis
  • p53
  • metabolism
  • disease treatment
  • tumor
  • ischemic organ injury
  • neurodegenerative disease
  • immune system function

Published Papers (13 papers)

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Research

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23 pages, 8513 KiB  
Article
Adverse Crosstalk between Extracellular Matrix Remodeling and Ferroptosis in Basal Breast Cancer
by Christophe Desterke, Emma Cosialls, Yao Xiang, Rima Elhage, Clémence Duruel, Yunhua Chang and Ahmed Hamaï
Cells 2023, 12(17), 2176; https://doi.org/10.3390/cells12172176 - 30 Aug 2023
Viewed by 1390
Abstract
(1) Background: Breast cancer is a frequent heterogeneous disorder diagnosed in women and causes a high number of mortality among this population due to rapid metastasis and disease recurrence. Ferroptosis can inhibit breast cancer cell growth, improve the sensitivity of chemotherapy and radiotherapy, [...] Read more.
(1) Background: Breast cancer is a frequent heterogeneous disorder diagnosed in women and causes a high number of mortality among this population due to rapid metastasis and disease recurrence. Ferroptosis can inhibit breast cancer cell growth, improve the sensitivity of chemotherapy and radiotherapy, and inhibit distant metastases, potentially impacting the tumor microenvironment. (2) Methods: Through data mining, the ferroptosis/extracellular matrix remodeling literature text-mining results were integrated into the breast cancer transcriptome cohort, taking into account patients with distant relapse-free survival (DRFS) under adjuvant therapy (anthracyclin + taxanes) with validation in an independent METABRIC cohort, along with the MDA-MB-231 and HCC338 transcriptome functional experiments with ferroptosis activations (GSE173905). (3) Results: Ferroptosis/extracellular matrix remodeling text-mining identified 910 associated genes. Univariate Cox analyses focused on breast cancer (GSE25066) selected 252 individual significant genes, of which 170 were found to have an adverse expression. Functional enrichment of these 170 adverse genes predicted basal breast cancer signatures. Through text-mining, some ferroptosis-significant adverse-selected genes shared citations in the domain of ECM remodeling, such as TNF, IL6, SET, CDKN2A, EGFR, HMGB1, KRAS, MET, LCN2, HIF1A, and TLR4. A molecular score based on the expression of the eleven genes was found predictive of the worst prognosis breast cancer at the univariate level: basal subtype, short DRFS, high-grade values 3 and 4, and estrogen and progesterone receptor negative and nodal stages 2 and 3. This eleven-gene signature was validated as regulated by ferroptosis inductors (erastin and RSL3) in the triple-negative breast cancer cellular model MDA-MB-231. (4) Conclusions: The crosstalk between ECM remodeling-ferroptosis functionalities allowed for defining a molecular score, which has been characterized as an independent adverse parameter in the prognosis of breast cancer patients. The gene signature of this molecular score has been validated to be regulated by erastin/RSL3 ferroptosis activators. This molecular score could be promising to evaluate the ECM-related impact of ferroptosis target therapies in breast cancer. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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19 pages, 6627 KiB  
Article
Erk1/2-Dependent HNSCC Cell Susceptibility to Erastin-Induced Ferroptosis
by Dragana Savic, Teresa Bernadette Steinbichler, Julia Ingruber, Giulia Negro, Bertram Aschenbrenner, Herbert Riechelmann, Ute Ganswindt, Sergej Skvortsov, József Dudás and Ira-Ida Skvortsova
Cells 2023, 12(2), 336; https://doi.org/10.3390/cells12020336 - 16 Jan 2023
Cited by 2 | Viewed by 3180
Abstract
Unfavorable clinical outcomes mean that cancer researchers must attempt to develop novel therapeutic strategies to overcome therapeutic resistance in patients with HNSCC. Recently, ferroptosis was shown to be a promising pathway possessing druggable targets, such as xCT (SLC7A11). Unfortunately, little is known about [...] Read more.
Unfavorable clinical outcomes mean that cancer researchers must attempt to develop novel therapeutic strategies to overcome therapeutic resistance in patients with HNSCC. Recently, ferroptosis was shown to be a promising pathway possessing druggable targets, such as xCT (SLC7A11). Unfortunately, little is known about the molecular mechanisms underlying the susceptibility of HNSCC cells to ferroptosis. The goal of this study was to determine whether HNSCC cells with activated Erk1/2 are vulnerable to ferroptosis induction. Our results have shown that xCT (SLC7A11) was overexpressed in malignant tissues obtained from the patients with HNSCC, whereas normal mucosa demonstrated weak expression of the protein. In order to investigate the role of Erk1/2 in the decrease in cell viability caused by erastin, xCT-overexpressing FaDu and SCC25 HNSCC cells were used. The ravoxertinib-dependent inhibition of Erk1/2 signaling led to the decrease in erastin efficacy due to the effect on ROS production and the upregulation of ROS scavengers SOD1 and SOD2, resulting in repressed lipid peroxidation. Therefore, it was concluded that the erastin-dependent activation of ferroptosis seems to be a promising approach which can be further developed as an additional strategy for the treatment of HNSCC. As ferroptosis induction via erastin is strongly dependent on the expression of Erk1/2, this MAP kinase can be considered as a predictor for cancer cells’ response to erastin. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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24 pages, 4754 KiB  
Article
Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia
by Huan Yang, Xuemei Zhang, Yubin Ding, Hui Xiong, Shaojian Xiang, Yang Wang, Huanhuan Li, Zheng Liu, Jie He, Yuelan Tao, Hongbing Yang and Hongbo Qi
Cells 2023, 12(1), 99; https://doi.org/10.3390/cells12010099 - 26 Dec 2022
Cited by 8 | Viewed by 2317
Abstract
Preeclampsia is a leading contributor to increased maternal morbidity and mortality in the perinatal period. Increasing evidence demonstrates that ferroptosis is an essential mechanism for the pathogenesis of preeclampsia. Elabela is a novel small-molecule polypeptide, mainly expressed in embryonic and transplacental tissues, with [...] Read more.
Preeclampsia is a leading contributor to increased maternal morbidity and mortality in the perinatal period. Increasing evidence demonstrates that ferroptosis is an essential mechanism for the pathogenesis of preeclampsia. Elabela is a novel small-molecule polypeptide, mainly expressed in embryonic and transplacental tissues, with an ability to promote cell proliferation and invasion. However, its specific regulatory mechanism in preeclampsia has not been completely elucidated. In this study, we first reveal an increased grade of ferroptosis accompanied by a downregulation of the expression of Elabela in preeclampsia placentas. We then confirm the presence of a ferroptosis phenotype in the placenta of the mouse PE-like model, and Elabela can reduce ferroptosis in the placenta and improve adverse pregnancy outcomes. Furthermore, we demonstrate that targeting Elabela alleviates the cellular dysfunction mediated by Erastin promoting increased lipid peroxidation in vitro. Subsequent mechanistic studies suggest that Elabela increases FTH1 levels by inhibiting the ferritinophagy pathway, and consequently chelates the intracellular labile iron pool and eventually arrests ferroptosis. In conclusion, Elabela deficiency exacerbates ferroptosis in the placenta, which is among the potential mechanisms in the pathogenesis of preeclampsia. Targeting the Elabela–ferritinophagy–ferroptosis signaling axis provides a new therapeutic intervention strategy to alleviate preeclampsia. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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22 pages, 4251 KiB  
Article
Targeting Wnt/β-Catenin Signaling Exacerbates Ferroptosis and Increases the Efficacy of Melanoma Immunotherapy via the Regulation of MITF
by Hao Wang, Hengxiang Zhang, Yuhan Chen, Huina Wang, Yangzi Tian, Xiuli Yi, Qiong Shi, Tao Zhao, Baolu Zhang, Tianwen Gao, Sen Guo, Chunying Li and Weinan Guo
Cells 2022, 11(22), 3580; https://doi.org/10.3390/cells11223580 - 12 Nov 2022
Cited by 10 | Viewed by 2439
Abstract
Melanoma is the most lethal form of skin cancer, resulting from the malignant transformation of epidermal melanocytes. Recent revolutionary progress in targeted therapy and immunotherapy has prominently improved the treatment outcome, but the survival of melanoma patients remains suboptimal. Ferroptosis is greatly involved [...] Read more.
Melanoma is the most lethal form of skin cancer, resulting from the malignant transformation of epidermal melanocytes. Recent revolutionary progress in targeted therapy and immunotherapy has prominently improved the treatment outcome, but the survival of melanoma patients remains suboptimal. Ferroptosis is greatly involved in cancer pathogenesis and can execute the outcome of immunotherapy. However, the detailed regulatory mechanisms of melanoma cell ferroptosis remain elusive. Herein, we report that Wnt/β-catenin signaling regulates ferroptosis and melanoma immunotherapy efficacy via the regulation of MITF. First of all, we found that Wnt/β-catenin signaling was prominently suppressed in melanoma cell ferroptosis. Then, we proved that targeting β-catenin exacerbated melanoma cell ferroptosis by promoting the generation of lipid peroxidation both in vitro and in vivo. Subsequent mechanistic studies revealed that MITF mediated the effect of Wnt/β-catenin signaling on melanoma cell ferroptosis, and PGC1α and SCD1 were documented as two main effectors downstream of Wnt/β-catenin-MITF pathway. Ultimately, pharmacological inhibition of β-catenin or MITF increased the efficacy of anti-PD-1 immunotherapy in preclinical xenograft tumor model by promoting ferroptosis. Taken together, Wnt/β-catenin signaling deficiency exacerbates ferroptosis in melanoma via the regulation of MITF. Targeting Wnt/β-catenin-MITF pathway could be a promising strategy to potentiate ferroptosis and increase the efficacy of anti-PD-1 immunotherapy. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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17 pages, 4167 KiB  
Article
Identification of SLC3A2 as a Potential Therapeutic Target of Osteoarthritis Involved in Ferroptosis by Integrating Bioinformatics, Clinical Factors and Experiments
by Hailong Liu, Zengfa Deng, Baoxi Yu, Hui Liu, Zhijian Yang, Anyu Zeng and Ming Fu
Cells 2022, 11(21), 3430; https://doi.org/10.3390/cells11213430 - 30 Oct 2022
Cited by 17 | Viewed by 3163
Abstract
Osteoarthritis (OA) is a type of arthritis that causes joint pain and limited mobility. In recent years, some studies have shown that the pathological process of OA chondrocytes is related to ferroptosis. Our study aims to identify and validate differentially expressed ferroptosis-related genes [...] Read more.
Osteoarthritis (OA) is a type of arthritis that causes joint pain and limited mobility. In recent years, some studies have shown that the pathological process of OA chondrocytes is related to ferroptosis. Our study aims to identify and validate differentially expressed ferroptosis-related genes (DEFRGs) in OA chondrocytes and to investigate the potential molecular mechanisms. RNA-sequencing and microarray datasets were downloaded from Gene Expression Omnibus (GEO) data repository. Differentially expressed genes (DEGs) were screened by four methods: limma-voom, edgeR, DESeq2, and Wilcoxon rank-sum test. Weighted correlation network analysis (WGCNA), protein-protein interactions (PPI), and cytoHubba of Cytoscape were applied to identify hub genes. Clinical OA cartilage specimens were collected for quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis, western blotting (WB), histological staining, transmission electron microscopy (TEM), and transfection. Sankey diagram was used to visualize the relationships between the expression level of SLC3A2 in the damaged area and clinical factors. Based on bioinformatics analysis, clinical factors, and experiment validation, SLC3A2 was identified as a hub gene. It was down-regulated in OA cartilage compared to normal cartilage (p < 0.05). Functional enrichment analysis revealed that SLC3A2 was associated with ferroptosis-related functions. Spearman correlation analysis showed that the expression level of SLC3A2 in the OA cartilage-damaged area was closely related to BMI, obesity grade, and Kellgren-Lawrence grade. Furthermore, in vitro experiments validated that SLC3A2 inhibited ferroptosis and suppressed cartilage degeneration in OA. In summary, we demonstrated that SLC3A2 inhibited ferroptosis and suppressed cartilage degeneration in OA. These findings provide a new idea for the study of the pathogenesis of OA, thus providing new means for the clinical diagnosis and targeted therapy of OA. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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27 pages, 9979 KiB  
Article
Maresin1 Suppresses High-Glucose-Induced Ferroptosis in Osteoblasts via NRF2 Activation in Type 2 Diabetic Osteoporosis
by Zhanwei Zhang, Chonghao Ji, Ya-Nan Wang, Shiyue Liu, Maoshan Wang, Xin Xu and Dongjiao Zhang
Cells 2022, 11(16), 2560; https://doi.org/10.3390/cells11162560 - 17 Aug 2022
Cited by 14 | Viewed by 3626
Abstract
Maresin1 (MaR1) is an endogenous pro-resolving lipid mediator produced from polyunsaturated fatty acids and is believed to have antioxidant and anti-inflammatory properties. The objective of this study was to estimate MaR1′s impact on type 2 diabetic osteoporosis (T2DOP) and its pharmacological mode of [...] Read more.
Maresin1 (MaR1) is an endogenous pro-resolving lipid mediator produced from polyunsaturated fatty acids and is believed to have antioxidant and anti-inflammatory properties. The objective of this study was to estimate MaR1′s impact on type 2 diabetic osteoporosis (T2DOP) and its pharmacological mode of action. An in vitro high-glucose model of the osteoblast cell line MC3T3-E1 was constructed and stimulated with MaR1. Type 2 diabetic rats were used to establish in vivo models of calvarial defects and were treated in situ with MaR1. The results revealed that, aside from preventing mortality and promoting the osteogenic capacity of MC3T3-E1 cells, MaR1 increased nuclear factor erythroid-2 related factor 2 (NRF2) signaling as well as the activity of glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11) and caused the restraint of ferroptosis under hyperglycemic stimulation. However, the therapeutic impact of MaR1 was significantly diminished due to NRF2-siRNA interference and the ferroptosis activator Erastin. Meanwhile, these results were validated through in vivo experiments. These findings imply that MaR1 activated the NRF2 pathway in vivo and in vitro to alleviate high-glucose-induced ferroptosis greatly. More crucially, MaR1 might effectively reduce the risk of T2DOP. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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20 pages, 7557 KiB  
Article
Ferroptosis-Related Genes Are Potential Therapeutic Targets and the Model of These Genes Influences Overall Survival of NSCLC Patients
by Na Zhang, Yangyang Wu, Yifan Wu, Lihong Wang, Jingfei Chen, Xiaosa Wang, Louisa S. Chard Dunmall, Zhenguo Cheng and Yaohe Wang
Cells 2022, 11(14), 2207; https://doi.org/10.3390/cells11142207 - 15 Jul 2022
Cited by 6 | Viewed by 2767
Abstract
Background: Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSCC) are two of the most common subtypes of non-small cell lung cancer (NSCLC), with high mortality rates and rising incidence worldwide. Ferroptosis is a mode of programmed cell death caused by lipid peroxidation, [...] Read more.
Background: Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSCC) are two of the most common subtypes of non-small cell lung cancer (NSCLC), with high mortality rates and rising incidence worldwide. Ferroptosis is a mode of programmed cell death caused by lipid peroxidation, the accumulation of reactive oxygen species, and is dependent on iron. The recent discovery of ferroptosis has provided new insights into tumor development, and the clinical relevance of ferroptosis for tumor therapy is being increasingly appreciated. However, its role in NSCLC remains to be explored. Methods: The clinical and molecular data for 1727 LUAD and LUSCC patients and 73 control individuals were obtained from the Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database. Gene expression profiles, copy number variations and somatic mutations of 57 ferroptosis-related genes in 1727 tumor samples from the four datasets were used in a univariate Cox analysis and consensus clustering analysis. The biological signatures of each pattern were identified. A ferroptosis score was generated by combining the univariate Cox regression analysis and random forest algorithm followed by principal component analysis (PCA) and further investigated for its predictive and therapeutic value in LUAD and LUSCC. Results: The expression of 57 ferroptosis-related genes in NSCLC patients differed significantly from that of normal subjects. Based on unsupervised clustering of ferroptosis-related genes, we divided all patients into three ferroptosis expression pattern groups, which showed differences in ferroptosis-associated gene expression patterns, immune cell infiltration levels, prognostic characteristics and enriched pathways. Using the differentially expressed genes in the three ferroptosis expression patterns, a set of 17 ferroptosis-related gene prognostic models was established, which clustered all patients in the cohort into a low score group and a high score group, with marked differences in prognosis (p < 0.001). The high ferroptosis score was significantly associated with positive response to radiotherapy (p < 0.001), high T stage (p < 0.001), high N stage (p < 0.001) and high-grade tumor (p < 0.001) characteristics. Conclusions: The 17 ferroptosis-associated genes show great potential for stratifying LUAD and LUSCC patients into high and low risk groups. Interestingly, a high ferroptosis score in LUAD patients was associated with a good prognosis, whereas a similar high ferroptosis score in LUSCC patients was associated with a poor prognosis. Familiarity with the mechanisms underlying ferroptosis and its implications for the treatment of NSCLC, as well as its effect on OS and PFS, may provide guidance and insights in developing new therapeutic targets for NSCLC. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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Review

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14 pages, 1661 KiB  
Review
Ferroptosis in Cancer Progression
by Rongyu Zhang, Jinghong Chen, Saiyang Wang, Wenlong Zhang, Quan Zheng and Rong Cai
Cells 2023, 12(14), 1820; https://doi.org/10.3390/cells12141820 - 10 Jul 2023
Cited by 4 | Viewed by 2108
Abstract
Ferroptosis is a newly discovered iron-dependent form of regulated cell death driven by phospholipid peroxidation and associated with processes including iron overload, lipid peroxidation, and dysfunction of cellular antioxidant systems. Ferroptosis is found to be closely related to many diseases, including cancer at [...] Read more.
Ferroptosis is a newly discovered iron-dependent form of regulated cell death driven by phospholipid peroxidation and associated with processes including iron overload, lipid peroxidation, and dysfunction of cellular antioxidant systems. Ferroptosis is found to be closely related to many diseases, including cancer at every stage. Epithelial–mesenchymal transition (EMT) in malignant tumors that originate from epithelia promotes cancer-cell migration, invasion, and metastasis by disrupting cell–cell and cell–cell matrix junctions, cell polarity, etc. Recent studies have shown that ferroptosis appears to share multiple initiators and overlapping pathways with EMT in cancers and identify ferroptosis as a potential predictor of various cancer grades and prognoses. Cancer metastasis involves multiple steps, including local invasion of cancer cells, intravasation, survival in circulation, arrest at a distant organ site, extravasation and adaptation to foreign tissue microenvironments, angiogenesis, and the formation of “premetastatic niche”. Numerous studies have revealed that ferroptosis is closely associated with cancer metastasis. From the cellular perspective, ferroptosis has been implicated in the regulation of cancer metastasis. From the molecular perspective, the signaling pathways activated during the two events interweave. This review briefly introduces the mechanisms of ferroptosis and discusses how ferroptosis is involved in cancer progression, including EMT, cancer angiogenesis, invasion, and metastasis. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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25 pages, 1173 KiB  
Review
Molecular Mechanisms of Ferroptosis and Updates of Ferroptosis Studies in Cancers and Leukemia
by Hiroki Akiyama, Bing Z. Carter, Michael Andreeff and Jo Ishizawa
Cells 2023, 12(8), 1128; https://doi.org/10.3390/cells12081128 - 11 Apr 2023
Cited by 10 | Viewed by 3582
Abstract
Ferroptosis is a mode of cell death regulated by iron-dependent lipid peroxidation. Growing evidence suggests ferroptosis induction as a novel anti-cancer modality that could potentially overcome therapy resistance in cancers. The molecular mechanisms involved in the regulation of ferroptosis are complex and highly [...] Read more.
Ferroptosis is a mode of cell death regulated by iron-dependent lipid peroxidation. Growing evidence suggests ferroptosis induction as a novel anti-cancer modality that could potentially overcome therapy resistance in cancers. The molecular mechanisms involved in the regulation of ferroptosis are complex and highly dependent on context. Therefore, a comprehensive understanding of its execution and protection machinery in each tumor type is necessary for the implementation of this unique cell death mode to target individual cancers. Since most of the current evidence for ferroptosis regulation mechanisms is based on solid cancer studies, the knowledge of ferroptosis with regard to leukemia is largely lacking. In this review, we summarize the current understanding of ferroptosis-regulating mechanisms with respect to the metabolism of phospholipids and iron as well as major anti-oxidative pathways that protect cells from ferroptosis. We also highlight the diverse impact of p53, a master regulator of cell death and cellular metabolic processes, on the regulation of ferroptosis. Lastly, we discuss recent ferroptosis studies in leukemia and provide a future perspective for the development of promising anti-leukemia therapies implementing ferroptosis induction. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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16 pages, 957 KiB  
Review
Ferroptosis: A New Development Trend in Periodontitis
by Kexiao Chen, Shuyuan Ma, Jianwen Deng, Xinrong Jiang, Fengyu Ma and Zejian Li
Cells 2022, 11(21), 3349; https://doi.org/10.3390/cells11213349 - 24 Oct 2022
Cited by 6 | Viewed by 2231
Abstract
Periodontitis is a chronic inflammatory disease associated with bacterial biofilm. It is characterized by loss of periodontal support tissue and has long been considered as a “silent disease”. Because it is difficult to prevent and has a health impact that can not be [...] Read more.
Periodontitis is a chronic inflammatory disease associated with bacterial biofilm. It is characterized by loss of periodontal support tissue and has long been considered as a “silent disease”. Because it is difficult to prevent and has a health impact that can not be ignored, researchers have been focusing on a mechanism-based treatment model. Ferroptosis is an iron-dependent regulatory form of cell death, that directly or indirectly affects glutathione peroxidase through different signaling pathways, resulting in a decrease in cell antioxidant capacity, accumulation of reactive oxygen species and lipid peroxidation, which cause oxidative cell death and tissue damage. Recently, some studies have proven that iron overload, oxidative stress, and lipid peroxidation exist in the process of periodontitis. Based on this, this article reviews the relationship between periodontitis and ferroptosis, in order to provide a theoretical reference for future research on the prevention and treatment of periodontal disease. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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14 pages, 2107 KiB  
Review
Molecular Mechanism of Ferroptosis in Orthopedic Diseases
by Lu Gao, Weizhong Hua, Lixiang Tian, Xuchang Zhou, Dongxue Wang, Yajing Yang and Guoxin Ni
Cells 2022, 11(19), 2979; https://doi.org/10.3390/cells11192979 - 24 Sep 2022
Cited by 15 | Viewed by 2848
Abstract
Ferroptosis is a new iron-dependent programmed cell death process that is directly mediated by the accumulation of lipid peroxides and reactive oxygen species. Numerous studies have shown that ferroptosis is important in regulating the occurrence and development of bone-related diseases, but the underlying [...] Read more.
Ferroptosis is a new iron-dependent programmed cell death process that is directly mediated by the accumulation of lipid peroxides and reactive oxygen species. Numerous studies have shown that ferroptosis is important in regulating the occurrence and development of bone-related diseases, but the underlying mechanisms are not completely clear. Herein, we review the progress of the mechanism of ferroptosis in bone marrow injury, osteoporosis, osteoarthritis, and osteosarcoma and attempt to deeply understand the regulatory targets of ferroptosis, which will open up a new way for the prevention and treatment of orthopedic diseases. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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13 pages, 1439 KiB  
Review
Ferroptosis: The Potential Target in Heart Failure with Preserved Ejection Fraction
by Qing Li, Zhiqiang Zhao, Xia Zhou, Yuting Yan, Lusi Shi, Jiafan Chen, Baohui Fu and Jingyuan Mao
Cells 2022, 11(18), 2842; https://doi.org/10.3390/cells11182842 - 12 Sep 2022
Cited by 6 | Viewed by 3837
Abstract
Ferroptosis is a recently identified cell death characterized by an excessive accumulation of iron-dependent reactive oxygen species (ROS) and lipid peroxides. Intracellular iron overload can not only cause damage to macrophages, endothelial cells, and cardiomyocytes through responses such as lipid peroxidation, oxidative stress, [...] Read more.
Ferroptosis is a recently identified cell death characterized by an excessive accumulation of iron-dependent reactive oxygen species (ROS) and lipid peroxides. Intracellular iron overload can not only cause damage to macrophages, endothelial cells, and cardiomyocytes through responses such as lipid peroxidation, oxidative stress, and inflammation, but can also affect cardiomyocyte Ca2+ handling, impair excitation–contraction coupling, and play an important role in the pathological process of heart failure with preserved ejection fraction (HFpEF). However, the mechanisms through which ferroptosis initiates the development and progression of HFpEF have not been established. This review explains the possible correlations between HFpEF and ferroptosis and provides a reliable theoretical basis for future studies on its mechanism. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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24 pages, 1876 KiB  
Review
Ferroptosis and Its Role in Chronic Diseases
by Wenli Hu, Kehong Liang, Hong Zhu, Chong Zhao, Hongbo Hu and Shutao Yin
Cells 2022, 11(13), 2040; https://doi.org/10.3390/cells11132040 - 27 Jun 2022
Cited by 26 | Viewed by 9385
Abstract
Ferroptosis, which has been widely associated with many diseases, is an iron-dependent regulated cell death characterized by intracellular lipid peroxide accumulation. It exhibits morphological, biochemical, and genetic characteristics that are unique in comparison to other types of cell death. The course of ferroptosis [...] Read more.
Ferroptosis, which has been widely associated with many diseases, is an iron-dependent regulated cell death characterized by intracellular lipid peroxide accumulation. It exhibits morphological, biochemical, and genetic characteristics that are unique in comparison to other types of cell death. The course of ferroptosis can be accurately regulated by the metabolism of iron, lipids, amino acids, and various signal pathways. In this review, we summarize the basic characteristics of ferroptosis, its regulation, as well as the relationship between ferroptosis and chronic diseases such as cancer, nervous system diseases, metabolic diseases, and inflammatory bowel diseases. Finally, we describe the regulatory effects of food-borne active ingredients on ferroptosis. Full article
(This article belongs to the Special Issue Novel Mechanisms and Therapeutic Opportunities of Ferroptosis)
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