Xin Wang
Jordan Lu2†
Guo Chen
Yanqing Liu- 1National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
- 2Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, United States
- 3School of Biopharmacy, China Pharmaceutical University, Nanjing, China
- 4Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
Editorial on the Research Topic
Ferroptosis in cancer and Beyond—volume II
Introduction
It has been 11 years since Brent Stockwell identified and named ferroptosis (Dixon et al., 2012). Ferroptosis results from iron-dependent lipoxidation at various cellular membrane structures. Searching the PubMed database by using the keyword “ferroptosis” results in more than 8,000 papers. Why has ferroptosis received such intensive attention? There are at least three fundamental reasons. First, ferroptosis has a unique mechanism distinct from other known regulated cell death types. Ferroptosis is tightly associated with cell metabolism, such as amino acid, iron, and ROS metabolism. There are three key elements for ferroptosis: substrate of lipid peroxidation, executor of lipid peroxidation, and anti-ferroptosis system (Liu and Gu, 2022a). The balance between the three elements dictates the sensitivity of a cell to ferroptosis. Second, there are multiple ways to induce ferroptosis meaning it has a complex regulatory network. Many pathways are involved in ferroptosis mediation. Key factors regulating ferroptosis, including GPX4, p53, FSP1, and ALOXs have been identified (Dixon and Stockwell, 2019; Liu et al., 2019; Liu and Gu, 2022a; Liu and Gu, 2022b). However, new pathways and regulators are still emerging. Third, ferroptosis participates in the regulation of numerous physiological or pathological processes, such as normal development, degenerative diseases, ischemic injuries, immune system activities, and particularly cancer. This means that ferroptosis has amazing potential as a therapeutic target in many diseases (Stockwell et al., 2020).
To examine progress in the ferroptosis field and advances in basic research and clinical applications focusing on ferroptosis, we launched a Research Topic named Ferroptosis in Cancer and Beyond in early 2022, which was a great success. Given the rapid progression in this field, we opened a second call for this same Research Topic in late 2022, which has now been successfully closed. This second volume brings together 13 papers, including 6 research articles and 7 reviews. These articles outline recent information about ferroptosis from both basic research and clinical translation angles. The papers are briefly introduced below.
To comprehensively understand the contribution of iron regulatory proteins (IRPs) to ferroptosis, McKale Montgomery and Cameron Cardona reviewed the regulatory processes regarding iron homeostasis, from absorption, metabolism to its participation in ferroptosis, and discussed the essential roles of various IRPs in ferroptosis and their potentials to be therapeutically maneuvered in cancer treatment. To explore how ferroptosis is regulated at the post-translational level, Zhang et al. introduce emerging evidence for the O-GlcNAc modification (O-GlcNAcylation) in ferroptosis in a review article and discuss the crosstalk between O-GlcNAcylation and ROS and related antioxidant defense systems. The authors elucidate the role of O-GlcNAcylation in proteins involved in iron metabolism and the regulation of lipid metabolism and peroxidation during ferroptosis. Furthermore, the underlying mechanisms including mitochondria dysfunction and endoplasmic reticulum alteration brought by O-GlcNAcylation are discussed. In their original research study, Nikulin et al. identified ELOVL5 and IGFBP6 may modulate the sensitivity of breast cancer cells to ferroptosis, possibly via enhancing the activity of GPX4, an antioxidant enzyme that plays a critical role in ferroptosis. Through analysis of the transcriptomic database and validation with HPLC-MS, the knockdown of either ELOVL5 or IGFBP6 was shown to cause remarkable changes in the production of long and very long fatty acids. In addition, the knockdown of ELOVL5 or IGFBP6 in MDA-MB-231 cells promotes cell death induced by PUFAs, and the potential benefit of PUFAs addition for improving chemotherapeutic effects was proposed in the condition of low IGFBP6 (and maybe ELOVL5) gene expression.
Glutathione S-transferase P1 (GSTP1) was proposed to be a potential target to tackle radioresistance in cancer therapy by Tan et al. GSTP1 is fundamental to maintaining cellular oxidative homeostasis and is involved in ferroptosis. Based on increasing evidence showing that iron metabolism, lipid peroxidation, and GSH level are modulated by radiotherapy, the authors elaborated on the potential to control GSTP1 levels to enhance the efficacy of radiotherapy in cancer treatment. More pathways in ferroptosis induced by radiotherapy and their implications for radiotherapy were reviewed by Giovanni Luca Beretta and Nadia Zaffaroni, and other strategies were proposed to improve the efficacy of radiotherapy, including enhancing ionizing radiation by other reagents or selectively inducing ferroptosis with metal-based nanoparticles. Lu et al. introduced all kinds of therapies for glioblastoma, including immunotherapy, radiotherapy, and chemotherapy, and discussed how ferroptosis participates and affects the efficacy of different therapeutic treatments. In an original research article, Shi et al. found that dihydroartemisinin (DHA), an adjuvant drug-enhancing chemotherapy, induced cervical cancer death via initiating ferroptosis and explored the involvement of ferritinophagy induced by DHA. Furthermore, DHA was also shown to have a synergistic role with doxorubicin (DOX) in promoting cervical cancer cell death.
Growing evidence has revealed the impact of T cell infiltration in the development of various types of cancer. Jiang et al. analyzed the differential gene expression in CD8+ T cells from CD8+ highly or low infiltrated samples in acute myeloid leukemia (AML) and conducted extensive bioinformatics analysis, and six ferroptosis-related genes (FRGs) were identified to generate a prognostic prediction model, which was validated to be helpful to risk stratification and prognostic prediction of AML patients. Han et al. identified several ferroptosis-related genes (FRGs) which correlate well with the immune microenvironment and establish a model to predict the prognosis of cervical cancer patients. Further mechanisms underlying iron homeostasis, ROS and lipid peroxidation, GPX4-GSH, and other regulator systems in cervical cancer were discussed in a review by Xiangyu Chang and Jinwei Miao. In another review, Lai et al. specifically elaborated on the influence of steroid hormone signaling on ferroptosis and discuss the involvement of ferroptosis in gynecologic cancers and potential therapies targeting ferroptosis for the treatment of gynecologic cancers.
With data from FerrDb and TCGA database, Li et al. established a prognostic prediction model for colorectal cancer (CRC) patients with 8 FRGs among which NOS2 is one of the most significantly affected examples and was validated with the CRC mouse model and the involvement of NF-κB pathway was elucidated. To investigate whether ferroptosis is associated with colon adenocarcinoma (COAD), Baldi et al. identified a 4-gene signature that distinguishes high-risk and low-risk patients, and those FRGs were further shown to be implicated in many pathological related pathways and a variety of miRNAs and transcription factors were found to be involved. These researches consolidated the idea that disease-associated cell death has a specific gene expression profile relevant to the prognosis of the patient (Liu et al., 2022; Ye et al., 2022; Liu et al., 2023).
Taken together, this second volume of the Research Topic Ferroptosis in Cancer and Beyond adds new knowledge to this field, furthering research and the clinical translation of ferroptosis.
Author contributions
XW: Writing–original draft. JL: Writing–original draft. GC: Writing–review and editing. CP: Writing–review and editing. YL: Conceptualization, Writing–original draft.
Acknowledgments
We are grateful to all the authors and reviewers for their contributions to this Research Topic.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., et al. (2012). Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149 (5), 1060–1072. doi:10.1016/j.cell.2012.03.042
Dixon, S. J., and Stockwell, B. R. (2019). The hallmarks of ferroptosis. Annu. Rev. Canc Biol. 3, 35–54. doi:10.1146/annurev-cancerbio-030518-055844
Liu, Y., and Gu, W. (2022a). p53 in ferroptosis regulation: the new weapon for the old guardian. Cell death Differ. 29 (5), 895–910. doi:10.1038/s41418-022-00943-y
Liu, Y., and Gu, W. (2022b). The complexity of p53-mediated metabolic regulation in tumor suppression. Seminars cancer Biol. 85, 4–32. doi:10.1016/j.semcancer.2021.03.010
Liu, Y. L. Y., Ye, S., Feng, H., and Ma, L. (2023). A new ferroptosis-related signature model including messenger RNAs and long non-coding RNAs predicts the prognosis of gastric cancer patients. J. Transl. Intern Med. 11 (2), 145–155. doi:10.2478/jtim-2023-0089
Liu, Y. Q., Liu, Y., Ye, S. J., Feng, H. J., and Ma, L. J. (2022). Development and validation of cuproptosis-related gene signature in the prognostic prediction of liver cancer. Front. Oncol. 12, 985484. doi:10.3389/fonc.2022.985484
Liu, Y. Q., Tavana, O., and Gu, W. (2019). p53 modifications: exquisite decorations of the powerful guardian. J. Mol. Cell Biol. 11 (7), 564–577. doi:10.1093/jmcb/mjz060
Stockwell, B. R., Jiang, X. J., and Gu, W. (2020). Emerging mechanisms and disease relevance of ferroptosis. Trends Cell Biol. 30 (6), 478–490. doi:10.1016/j.tcb.2020.02.009
Keywords: ferroptosis, oxidative stress, cancer, iron, disease treatment
Citation: Wang X, Lu J, Chen G, Pan C and Liu Y (2023) Editorial: Ferroptosis in cancer and Beyond—volume II. Front. Mol. Biosci. 10:1265127. doi: 10.3389/fmolb.2023.1265127
Received: 22 July 2023; Accepted: 25 July 2023;
Published: 29 August 2023.
Edited and reviewed by:
William C. Cho, QEH, Hong Kong SAR, ChinaCopyright © 2023 Wang, Lu, Chen, Pan and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Guo Chen, gchen84@cpu.edu.cn; Chaoyun Pan, panchy27@mail.sysu.edu.cn; Yanqing Liu, lyanqing321@163.com
†These authors have contributed equally to this work