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Regulation and Targeting of Ferroptosis in Tumor and Beyond

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 6890

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Special Issue Editors

Dr. Yong Teng

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Guest Editor

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
Interests: metastasis; molecular pathway; cancer models; metabolism; tumor microenvironment, drug screening and development
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Jin Xie

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Guest Editor

Department of Chemistry and Bio-Imaging Research Center (BIRC), University of Georgia, Athens, GA 30602, USA
Interests: analytical chemistry; inorganic chemistry

Special Issue Information

Dear Colleagues,

Ferroptosis is a newly emerged programmed necrosis process implicated in multiple biological and pathological conditions. As a novel form of regulated cell death (RCD), ferroptosis has garnered increasing attention in studies on numerous human diseases in the last decade. Numerous cellular factors and potential regulatory pathways underlying ferroptosis have been elucidated; however, its precise mechanism and function are not well understood. Emerging evidence has demonstrated that ferroptosis is an iron-dependent form of nonapoptotic cell death induced by excessive lipid peroxidation, which is accompanied by an increased uptake of polyunsaturated fatty acids into the cellular membrane and further unfolding an ancient vulnerability in multiple contexts. Ferroptosis susceptibility has been demonstrated in many cancers, including hepatocellular carcinoma, breast cancer, and head and neck cancer. Ferroptosis induction, a nonapoptotic, regulated cell death modality, is a promising anti-cancer strategy.

The main aim of this Topic is to study the mechanistic underpinnings of ferroptosis. Those include how ferroptosis is regulated at the molecular level and how to target its pathways therapeutically. Here we will pay extra attention to these articles about novel/non-canonical ferroptosis pathways. This SI aims to advance our understanding of the fundamental biological process of ferroptosis and potentially identify new approaches to manipulate it for therapeutic benefits. Original Research Articles, Reviews, and Mini-Reviews are welcome to submit to this Research Topic. Papers are expected to cover but are not limited to the following topics:

Basic mechanisms involved in ferroptosis and critical regulators of ferroptosis.
The role of proto-oncogenes and tumor suppressor genes in canonical and non-canonical ferroptosis regulation.
Targeting ferroptosis for disease treatment.
Ferroptosis and immunotherapy.
Ferroptosis and cellular metabolism.
Studies related to other cell death mechanisms (including but not limited to pyroptosis, apoptosis, necroptosis, and PANoptosis).
The role of ferroptosis in drug resistance and stem cells.
New drugs and targeting therapeutics associated with ferroptosis.

Dr. Yong Teng
Prof. Dr. Jin Xie
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ferroptosis
iron
tumor survival and cell death
oxidation
drug development
anticancer strategies

Published Papers (5 papers)

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Research

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25 pages, 6065 KiB

Open AccessArticle

Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome

by Timothy Horseman, W. Bradley Rittase, John E. Slaven, Dmitry T. Bradfield, Andrew M. Frank, Joseph A. Anderson, Evelyn C. Hays, Andrew C. Ott, Anjali E. Thomas, Alison R. Huppmann, Sang-Ho Lee, David M. Burmeister and Regina M. Day

Int. J. Mol. Sci. 2024, 25(8), 4535; https://doi.org/10.3390/ijms25084535 - 20 Apr 2024

Viewed by 901

Abstract

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril’s effects on the GI following TBI (⁶⁰Co 1.79 or 1.80 Gy, 0.42–0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI. Full article

(This article belongs to the Special Issue Regulation and Targeting of Ferroptosis in Tumor and Beyond)

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17 pages, 5660 KiB

Open AccessArticle

SARS-CoV-2 Accessory Protein Orf7b Induces Lung Injury via c-Myc Mediated Apoptosis and Ferroptosis

by Rushikesh Deshpande, Wangyang Li, Tiao Li, Kristen V. Fanning, Zachary Clemens, Toru Nyunoya, Lianghui Zhang, Berthony Deslouches, Aaron Barchowsky, Sally Wenzel, John F. McDyer and Chunbin Zou

Int. J. Mol. Sci. 2024, 25(2), 1157; https://doi.org/10.3390/ijms25021157 - 18 Jan 2024

Cited by 2 | Viewed by 1456

Abstract

The pandemic of coronavirus disease 2019 (COVID-19) has been the foremost modern global public health challenge. The airway is the primary target in severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection, with substantial cell death and lung injury being signature hallmarks of exposure. The viral factors that contribute to cell death and lung injury remain incompletely understood. Thus, this study investigated the role of open reading frame 7b (Orf7b), an accessory protein of the virus, in causing lung injury. In screening viral proteins, we identified Orf7b as one of the major viral factors that mediates lung epithelial cell death. Overexpression of Orf7b leads to apoptosis and ferroptosis in lung epithelial cells, and inhibitors of apoptosis and ferroptosis ablate Orf7b-induced cell death. Orf7b upregulates the transcription regulator, c-Myc, which is integral in the activation of lung cell death pathways. Depletion of c-Myc alleviates both apoptotic and ferroptotic cell deaths and lung injury in mouse models. Our study suggests a major role of Orf7b in the cell death and lung injury attributable to COVID-19 exposure, supporting it as a potential therapeutic target. Full article

(This article belongs to the Special Issue Regulation and Targeting of Ferroptosis in Tumor and Beyond)

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Review

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25 pages, 2828 KiB

Open AccessReview

Ferroptosis: Frenemy of Radiotherapy

by Lisa Kerkhove, Febe Geirnaert, Inès Dufait and Mark De Ridder

Int. J. Mol. Sci. 2024, 25(7), 3641; https://doi.org/10.3390/ijms25073641 - 25 Mar 2024

Cited by 1 | Viewed by 891

Abstract

Recently, it was established that ferroptosis, a type of iron-dependent regulated cell death, plays a prominent role in radiotherapy-triggered cell death. Accordingly, ferroptosis inducers attracted a lot of interest as potential radio-synergizing drugs, ultimately enhancing radioresponses and patient outcomes. Nevertheless, the tumor microenvironment seems to have a major impact on ferroptosis induction. The influence of hypoxic conditions is an area of interest, as it remains the principal hurdle in the field of radiotherapy. In this review, we focus on the implications of hypoxic conditions on ferroptosis, contemplating the plausibility of using ferroptosis inducers as clinical radiosensitizers. Furthermore, we dive into the prospects of drug repurposing in the domain of ferroptosis inducers and radiosensitizers. Lastly, the potential adverse effects of ferroptosis inducers on normal tissue were discussed in detail. This review will provide an important framework for subsequent ferroptosis research, ascertaining the feasibility of ferroptosis inducers as clinical radiosensitizers. Full article

(This article belongs to the Special Issue Regulation and Targeting of Ferroptosis in Tumor and Beyond)

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20 pages, 2374 KiB

Open AccessReview

Ferroptosis, Metabolic Rewiring, and Endometrial Cancer

by Eglė Žalytė

Int. J. Mol. Sci. 2024, 25(1), 75; https://doi.org/10.3390/ijms25010075 - 20 Dec 2023

Viewed by 1237

Abstract

Ferroptosis is a newly discovered form of regulated cell death. The main feature of ferroptosis is excessive membrane lipid peroxidation caused by iron-mediated chemical and enzymatic reactions. In normal cells, harmful lipid peroxides are neutralized by glutathione peroxidase 4 (GPX4). When GPX4 is inhibited, ferroptosis occurs. In mammalian cells, ferroptosis serves as a tumor suppression mechanism. Not surprisingly, in recent years, ferroptosis induction has gained attention as a potential anticancer strategy, alone or in combination with other conventional therapies. However, sensitivity to ferroptosis inducers depends on the metabolic state of the cell. Endometrial cancer (EC) is the sixth most common cancer in the world, with more than 66,000 new cases diagnosed every year. Out of all gynecological cancers, carcinogenesis of EC is mostly dependent on metabolic abnormalities. Changes in the uptake and catabolism of iron, lipids, glucose, and glutamine affect the redox capacity of EC cells and, consequently, their sensitivity to ferroptosis-inducing agents. In addition to this, in EC cells, ferroptosis-related genes are usually mutated and overexpressed, which makes ferroptosis a promising target for EC prediction, diagnosis, and therapy. However, for a successful application of ferroptosis, the connection between metabolic rewiring and ferroptosis in EC needs to be deciphered, which is the focus of this review. Full article

(This article belongs to the Special Issue Regulation and Targeting of Ferroptosis in Tumor and Beyond)

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16 pages, 1258 KiB

Open AccessReview

Iron, Ferroptosis, and Head and Neck Cancer

by Yong Teng, Lixia Gao, Antti A. Mäkitie, Ewa Florek, Agata Czarnywojtek, Nabil F. Saba and Alfio Ferlito

Int. J. Mol. Sci. 2023, 24(20), 15127; https://doi.org/10.3390/ijms242015127 - 12 Oct 2023

Cited by 1 | Viewed by 1674

Abstract

Ferroptosis is an iron-dependent regulatory form of cell death characterized by the accumulation of intracellular reactive oxygen species and lipid peroxidation. It plays a critical role not only in promoting drug resistance in tumors, but also in shaping therapeutic approaches for various malignancies. This review aims to elucidate the relationship between ferroptosis and head and neck cancer treatment by discussing its conceptual framework, mechanism of action, functional aspects, and implications for tumor therapy. In addition, this review consolidates strategies aimed at improving the efficacy of head and neck cancer treatment through modulation of ferroptosis, herein serving as a valuable reference for advancing the treatment landscape for this patient population. Full article

(This article belongs to the Special Issue Regulation and Targeting of Ferroptosis in Tumor and Beyond)

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