Yongyi Liang
Zhenyi Su
Xiaoyuan Mao
Shibiao Wan
Lianxiang Luo- 1The First Clinical College, Guangdong Medical University, Zhanjiang, China
- 2Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, United States
- 3Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- 4Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, United States
- 5The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China
- 6The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, China
Editorial on the Research Topic
Ferroptosis as a novel therapeutic target for inflammation-related diseases
Ferroptosis was first proposed in 2012 as a relatively new mode of cell death (Dixon et al., 2012). It is driven by iron-dependent lipid peroxidation, which is a programmed cell death distinct from apoptosis, various forms of necrosis, and autophagy. At the ultrastructural level, ferroptotic cells usually exhibit mitochondrial abnormalities (Tang et al., 2021). There are shared features in ferroptosis and inflammatory diseases, including Depletion of glutathione peroxidase four and glutathione, elevated lipid peroxidation products, as well as disrupted iron metabolism (Mao et al., 2020). As the process of a systemic response, inflammation can be protective or pathological. Inflammatory biology is associated with almost all human diseases (Medzhitov, 2021).
Ferroptosis is closely related to inflammation. Traces of inflammation can be easily captured in pathologies involving ferroptosis (Stockwell, 2022). Ferroptosis is accompanied by the release of proinflammatory molecules, such as interleukin (IL)-1β and IL-18 (Sun et al., 2020). Meanwhile, ferroptosis exacerbates the inflammatory response to varying degrees through mediators such as ferroptosis regulators like glutathione peroxidase 4, reactive oxygen species, lipoxygenases, and inflammatory mediators produced during ferroptosis (Deng et al., 2022). Several anti-inflammatory drugs have been shown to inhibit ferroptosis in certain cellular models (Wang et al., 2023). However, studies exploring the role of ferroptosis in inflammation are still scarce, though the research field of ferroptosis has been enjoying exponential growth over the past few years (Jiang et al., 2021), especially in cancer treatment (Chen et al., 2021). Nanomaterials targeting ferroptosis-based cancer therapy have shown considerable promise (Luo et al., 2021). Our Research Topic includes four reviews and three original articles studying ferroptosis and inflammatory diseases, as well as related drugs that contribute to the regulation of ferroptosis for the treatment of inflammatory diseases.
Many inflammatory diseases are associated with ferroptosis, such as acute renal failure, Acute lung injury, neurodegenerative diseases, chronic autoimmune diseases of the gastrointestinal, etc. (Deng et al., 2022). A review by Zhang et al. reported that inflammatory-associated intestinal diseases are strongly associated with ferroptosis, indicating that ferroptosis may act as potential therapeutic targets for inflammatory-associated intestinal diseases. In addition, some inflammatory diseases are infectious, such as COVID-19. Iron overload is a contributing factor to COVID-19. If left untreated, ferroptosis can promote a range of responses that enhance inflammation, leading to multi-organ failure, lung injury, and reduced lung capacity (Habib et al., 2021). A review by Xiao et al. summarized the mechanisms of ferroptosis, elucidated the role of ferroptosis in the onset and progression of different infectious diseases. At the same time, it suggested that ferroptosis may be a new therapeutic target for the development of more effective adjuvant therapies for infectious diseases. Based the relationship between ferroptosis and inflammation, researchers have found that anti-inflammatory drugs can inhibit ferroptosis. It has been demonstrated that the anti-inflammatory drug quercetin may inhibit ferroptosis, via the PI3K/AKT/mTOR pathway (Lan et al., 2022). L-cit, which has anti-inflammatory properties, may target ferritin phagocytosis and mediate ferroptosis (Ba et al., 2022). A review by Li et al. described the active glycoside component of the medicinal plant Anoectochilus roxburghii, kinsenoside (KD), which also has potent anti-inflammatory and antioxidant properties. It summarized the multiple actions of KD and suggested that it may regulate ferroptosis. Another review by Zeng et al. investigated the effects of various anesthetics on molecular mechanisms and signaling pathways related to ferroptosis. The authors hypothesized that the mechanism of action of anesthetics varies across experiments and different cellular systems because of the paradoxical nature of anesthetics to inhibit ferroptosis in inflammatory disease models but promote ferroptosis in tumor cells. It may exhibit anti-inflammatory and anti-ferroptosis effects in inflammatory diseases such as IRI.
In the meantime, the three original articles in our Research Topic also focused on the study of iron death and inflammatory diseases and related drugs. Xu et al. predicted a signature for acute coronary syndrome (ACS) based on the expression levels of genes related to iron metabolism and identified novel serum iron gene markers in the early stages of ACS. Five genes, namely, PADI4, HLA-DQA1, LCN2, CD7 and VNN1, were selected by using a feature-selection method called Elastic Net and included in the final Immune Gene Signature model. Pan et al. used integrated bioinformatics to analyze ferroptosis, necroptosis and scorch-related genes in periodontitis-affected periodontitis tissues to obtain 21 differential genes, together with their associated cellular and immune pathways. Among them, SLC2A3 was associated with ferroptosis. The upregulation of SLC2A3 was positively correlated with periodontal neutrophil infiltration. Herbal medicine may have a significant role in the regulation of ferroptosis (Gao et al., 2022). HJ11 is a novel Chinese medicine derived from the appropriate addition and reduction of Si Miao Yong An Tang. Zhang et al. presented a model of myocardial ischemia-reperfusion (I/R) injury in rats and demonstrated that HJ11 decoction inhibits the development of myocardial I/R injury by regulating ACSL4-mediated ferroptosis. Thus, HJ11 soup may be an effective drug for the treatment of myocardial I/R injury.
In conclusion, ferroptosis is highly correlated with inflammation, for which one potential way to treat inflammatory diseases is based on regulating ferroptosis. The discovery and study of various drugs that modulate ferroptosis have brought new hope to the clinical treatment of inflammatory diseases. The studies in this Research Topic provide evidence for the important role of ferroptosis in the treatment of inflammation, elaborate the specific mechanisms of ferroptosis action in some diseases. It also shows that many ferroptosis-related genes and molecules can serve as key targets for disease treatment. Meanwhile, drug discovery and research have provided new directions for the regulation of ferroptosis. However, questions such as how to maximize the use of ferroptosis to minimize the harm to patients, how to grasp the time point of drug intervention and the exact dosage, and the different regulatory effects of drugs on ferroptosis in tumor cells and inflammatory cells are still waiting for researchers to explore.
Author contributions
LL conceived and designed the editorial; YL, SW and LL wrote the editorial; LL, XM, SW and ZS reviewed the paper and provided comments. All authors read and approved the final manuscript.
Funding
This work was supported by the Buffet Cancer Center, which is supported by the National Cancer Institute under award number CA036727, in collaboration with the UNMC/Children’s Hospital & Medical Center Child Health Research Institute Pediatric Cancer Research Group.
Acknowledgments
We thank all the authors, reviewers and editors who contributed 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
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References
Ba, T., Zhao, D., Chen, Y., Zeng, Y., Zhang, C., Niu, S., et al. (2022). L-Citrulline supplementation restrains ferritinophagy-mediated ferroptosis to alleviate iron overload-induced thymus oxidative damage and immune dysfunction. Nutrients 14 (21), 4549. doi:10.3390/nu14214549
Chen, X., Kang, R., Kroemer, G., and Tang, D. (2021). Broadening horizons: The role of ferroptosis in cancer. Nat. Rev. Clin. Oncol. 18, 280–296. doi:10.1038/s41571-020-00462-0
Deng, L., He, S., Guo, N., Tian, W., Zhang, W., and Luo, L. (2022). Molecular mechanisms of ferroptosis and relevance to inflammation. Inflamm. Res. 1, 1–19. doi:10.1007/s00011-022-01672-1
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 non-apoptotic cell death. Cell 149, 1060–1072. doi:10.1016/j.cell.2012.03.042
Gao, Q., Yin, X., Zhang, F., Zhu, Y.-Z., and Li, Z. (2022). The regulatory effects of traditional Chinese medicine on ferroptosis. Oxid. Med. Cell Longev. 2022, 4578381. doi:10.1155/2022/4578381
Habib, H. M., Ibrahim, S., Zaim, A., and Ibrahim, W. H. (2021). The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators. Biomed. Pharmacother. 136, 111228. doi:10.1016/j.biopha.2021.111228
Jiang, X., Stockwell, B. R., and Conrad, M. (2021). Ferroptosis: Mechanisms, biology, and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266–282. doi:10.1038/s41580-020-00324-8
Lan, D., Qi, S., Yao, C., Li, X., Liu, H., Wang, D., et al. (2022). Quercetin protects rat BMSCs from oxidative stress via ferroptosis. J. Mol. Endocrinol. 69 (3), 401–413. doi:10.1530/JME-22-0086
Luo, L., Wang, H., Tian, W., Li, X., Zhu, Z., Huang, R., et al. (2021). Targeting ferroptosis-based cancer therapy using nanomaterials: Strategies and applications. Theranostics 11, 9937–9952. doi:10.7150/thno.65480
Mao, H., Zhao, Y., Li, H., and Lei, L. (2020). Ferroptosis as an emerging target in inflammatory diseases. Prog. Biophys. Mol. Biol. 155, 20–28. doi:10.1016/j.pbiomolbio.2020.04.001
Medzhitov, R. (2021). The spectrum of inflammatory responses. Science 374, 1070–1075. doi:10.1126/science.abi5200
Stockwell, B. R. (2022). Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401–2421. doi:10.1016/j.cell.2022.06.003
Sun, Y., Chen, P., Zhai, B., Zhang, M., Xiang, Y., Fang, J., et al. (2020). The emerging role of ferroptosis in inflammation. Biomed. Pharmacother. 127, 110108. doi:10.1016/j.biopha.2020.110108
Tang, D., Chen, X., Kang, R., and Kroemer, G. (2021). Ferroptosis: Molecular mechanisms and health implications. Cell Res. 31, 107–125. doi:10.1038/s41422-020-00441-1
Keywords: ferroptosis, inflammation-related diseases, lipid peroxidation, inflammatory mediators, immunomodulatory
Citation: Liang Y, Su Z, Mao X, Wan S and Luo L (2023) Editorial: Ferroptosis as a novel therapeutic target for inflammation-related diseases. Front. Pharmacol. 14:1152326. doi: 10.3389/fphar.2023.1152326
Received: 27 January 2023; Accepted: 30 January 2023;
Published: 16 February 2023.
Edited and reviewed by:
Paola Patrignani, University of Studies G.d'Annunzio Chieti and Pescara, ItalyCopyright © 2023 Liang, Su, Mao, Wan and Luo. 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: Shibiao Wan, swan@unmc.edu; Lianxiang Luo, luolianxiang321@gdmu.edu.cn