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. 2022 May 25;10:841724. doi: 10.3389/fcell.2022.841724

The Research Landscape of Ferroptosis in Cancer: A Bibliometric Analysis

Guoli Li 1,2,3, Yumei Liang 1,2,3, Hongyu Yang 4,5,6, Weiru Zhang 4,5,6, Tingting Xie 4,5,6,*
PMCID: PMC9174675  PMID: 35693942

Abstract

Background: Ferroptosis is a novel mechanism of programmed cell death coined in 2012, which has been found to play important roles in human health and disease. In the past decade, ferroptosis research has seen booming growth worldwide. The aim of this study was to visualize the scientific outputs and research trends of ferroptosis in the field of cancer.

Methods: The raw data of publications were retrieved from the Web of Science Core Collection on 19 December 2021. The information on the impact factor (IF) and Journal Citation Reports (JCR) division were obtained from the website of Web of Science. Two kinds of software (CiteSpace and VOSviewer) were used to perform visualized analysis.

Results: From 2012 to 2021, a total of 1833 publications related to ferroptosis in cancer were identified for final analysis. The annual number of citations and publications grew exponentially over the past decade. China (1,092) and United States (489) had the highest number of publications; Central South University and Guangzhou Medical University were the most productive institutions. Daolin Tang and Scott J Dixon were the most active authors ranked by most productive and co-cited, respectively. The journals with the highest output and co-citation frequency were Biochemical and Biophysical Research Communications and Cell, respectively. Among the 1833 publications, four were identified with citations more than 1000 times. Six co-cited references had a citation burst duration until 2021. Analysis of keywords suggested the current research of ferroptosis in cancer clusters in 9 hotspots and newly emerging frontier may be “multidrug resistance”.

Conclusion: Cancer research is the major area of active research in ferroptosis. Our results provide a global landscape of the ferroptosis research in cancer from 2012 to 2021, which serves as a reference for future studies in this field.

Keywords: ferroptosis, cancer, bibliometric analysis, citespace, VOSviewer, visualization

Introduction

Ferroptosis, a term coined fairly by Dixon et al., in 2012, is a form of programmed non-apoptotic cell death characterized by iron-dependent lipid peroxidation (Dixon et al., 2012). Since then, much attention has been attracted to the research field of biomedicine over the past decade. To date, ferroptosis has been reported in a series of human diseases, including carcinogenesis(Chen et al., 2021b), aging-related diseases(Jenkins et al., 2020; Yan et al., 2021), ischemia-reperfusion injury(Stockwell et al., 2017; Yan et al., 2022), and cardiovascular diseases(Zhang et al., 2021d). It has gradually become a hotspot and rising star in biomedical research.

Unlike other types of regulated cell death, there are three distinct biochemical hallmarks of ferroptosis: accumulation of redox-active iron, induction of lipid peroxidation, and loss of antioxidant defense (Dixon and Stockwell, 2019). Together, these events contribute to the unrestrained phospholipid peroxidation (PLOOHs), which sequentially leads to the plasma membrane rupture and initiated the process of ferroptosis (Jiang et al., 2021). Although the exact molecular mechanism of ferroptosis is not yet fully understood, several key regulators (such as glutathione peroxidase 4 and system xc – cystine/glutamate antiporter) and pathways (such as Hippo–YAP, AMPK, and hypoxia pathways) have been convincingly established and recently reviewed (Dixon and Stockwell, 2019; Hadian and Stockwell, 2020; Chen et al., 2021a; Chen et al., 2021b; Jiang et al., 2021).

Cancer, a disease resulting from abnormal cell proliferation, has become a major public health problem worldwide (Sung et al., 2021). The balance between cell death and survival is directly linked to the development of cancer and regulated by programmed cell death mechanisms including apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis(Strasser and Vaux, 2020). Actually, the initial discovery of ferroptosis is the result of screening novel small molecule compounds for anticancer therapies(Dolma et al., 2003). Since then, cancer-related research has been extensively conducted in the context of ferroptosis. Emerging evidence implicated that the role of ferroptosis in cancer is complex and context-dependent with both promotion and suppression effects in tumorigenesis(Chen et al., 2021b). Preliminary findings suggested that triggering ferroptosis holds great potential for the development of cancer treatment including chemotherapy, radiotherapy, immunotherapy, and nano therapy (Shen et al., 2018; Liang et al., 2019; Chen et al., 2021b; Lei et al., 2021).

The term bibliometric was coined in 1969 by Alan Pritchard (Pritchard, 1969). Bibliometric analysis is a powerful tool that uses literature metrics or indicators to quantitively measure the research performance in a certain field (Deng et al., 2020; Wang et al., 2021). CiteSpace and VOSviewer are two commonly used visualizing processing tools for bibliometric analysis (Moral-Muñoz et al., 2020). A good bibliometric analysis can help researchers get the research hotspots and advances timely and comprehensively (Chen et al., 2020).In addition, compared to traditional review, the bibliometric analysis is more intuitive. Previously, several traditional reviews have described the roles of ferroptosis in cancer (Shen et al., 2018; Hassannia et al., 2019; Liang et al., 2019; Chen et al., 2021b). However, to our best knowledge, no bibliometric studies have been performed in the field of ferroptosis research in cancer.

Herein, to draw a full map of ferroptosis research trends in the field of cancer, we performed a bibliometric analysis of publication output, distribution across countries/regions and institutions, contribution of authors and journals, and the most frequently cited papers and appeared keywords. Our results provided a comprehensive understanding of development in the research field of ferroptosis in cancer, which may help future researchers.

Materials and Methods

Data Collection

Raw data were extracted from the database of Web of Science Core Collection. The literature search was performed within 1 day on 19 December 2021. The search formula was set as follows: ferroptosis (Topic) and “tumor*” or “cancer*” or “carcino*” or “onco*” (All Fields) and 2012–2021 (Year Published) and Meeting Abstracts or Editorial Materials or Early Access or Book Chapters or Corrections or News Items or Letters or Proceedings Papers or Retractions or Retracted Publications (Exclude—Document Types). A total of 1836 works of literature were obtained and exported for full record and cited references in the format of plain text files. Using Endnote software, three duplications were found. After removing duplications, a total of 1833 unique records remained, including 1,381 articles and 452 reviews (Supplementary Table S1).

Visualized Analysis

CiteSpace software (Drexel University, Philadelphia, PA, United States) is a freely available Java application, which was widely used for visualizing and analyzing trends and patterns in the scientific literature (Chen, 2006). It was designed by Dr. Chaomei Chen in 2004 (Chen, 2004) and last updated on 17 January 2021 (Version 5.8.R2) (http://cluster.cis.drexel.edu/∼cchen/citespace/). Web of Science was the primary source of input data for CiteSpace. In this study, CiteSpace was used to get the map of network visualization (Countries/Regions, Institutions, Authors), the timeline view of co-occurrence (Keywords), and citation bursts (References and Keywords). The primary parameters were set as follows: time slicing (2012–2021), years per slice (1 year), selection criteria (g-index, k = 25), and pruning (minimum spanning tree, pruning sliced networks). Other parameters were set according to the CiteSpace manual for different situations.

VOSviewer software is a useful tool for constructing and visualizing bibliometric networks (van Eck and Waltman, 2010). It was developed by the Center for Science and Technology Research at Leiden University (Netherlands) in 2007 (van Eck and Waltman, 2007). The latest version 1.6.17 was released on 22 July 2021 and is free for download (https://www.vosviewer.com/). Co-authorship networks, citation-based networks, and co-occurrence networks can be created based on data downloaded from the Web of Science. In this study, VOSviewer was used to get the density map of co-cited authors, co-cited journals, and the co-occurrence of keywords.

Other information such as impact factor (IF) and Journal Citation Reports (JCR) division of journals were obtained from the Web of Science website directly on 19 November 2021. Microsoft Office Excel 2016 was used to analyze the annual publications. GraphPad Prism version 8 was used for statistical analysis. Pearson’s correlation analysis was used to investigate relationships between the annual publication numbers and annual citation numbers. A p value of <0.05 was considered statistically significant.

Results

Trends in Publication Outputs

From the first paper published on 25 May 2012 to 19 December 2021, a total of 1833 publications related to ferroptosis in cancer were identified. Figure 1; Table 1 showed the annual number of publications of ferroptosis in cancer. In general, the annual number of publications increased year by year. The early stage (2012–2017) saw a relatively stable growth, with a publication counts of no more than 100 per year. While a steep growth of annual publication numbers was observed since 2018, approximately doubling every year. Up to date (19 December 2021), the publication outputs have reached over 846 in 2021. Compared to other fields of ferroptosis, the publications on ferroptosis in cancer account for most of the total publications annually (Table 1; Supplementary Figure S1). The prediction analysis indicated that over 3,500 papers will be published in 2025 (Supplementary Figure S2). As the number of citations also reflects research progress in a field (Waltman, 2016), citation analysis was performed in parallel. Similar to the trend of annual publication numbers, the annual citation numbers increased exponentially in the past decade (Figure 1). Indeed, the annual number of citations and publications was significantly correlated (Pearson r = 0.9994, p-value < 0.0001) (Supplementary Figure S3).

FIGURE 1.

FIGURE 1

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Number of annual publications and citations of ferroptosis in cancer from 2012 to 2021.

TABLE 1.

The annual number of publications on ferroptosis.

Ferroptosis in cancer Ferroptosis in all fields
Year Count % of 1,833 Citation Count % of 2,805 Citation
2012 1 0.05 8 1 0.04 8
2013 2 0.11 25 5 0.18 31
2014 14 0.76 168 16 0.57 183
2015 20 1.09 424 27 0.96 457
2016 53 2.89 1,111 63 2.25 1,207
2017 71 3.87 1885 96 3.42 2,102
2018 121 6.60 3,632 182 6.49 4,195
2019 231 12.60 8,228 360 12.83 9,713
2020 474 25.86 17,276 738 26.31 20,981
2021 846 46.15 32,140 1,317 46.95 39,630
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Geographical Distribution of the Publications

VOSviewer co-authorship analysis among the countries/regions was conducted to generate a network visualization map. Geographically, a total of 1833 articles were published from 63 different countries/regions covering five continents. Notably, Taiwan and the People’s Republic of China were merged into China; England, Scotland, Northern Ireland, and Wales were merged into the United Kingdom. To make the network clear, only 23 selected countries/regions that published at least 10 documents were visualized in Figure 2A. A complete list of documents, citations, and total link strength of the 63 countries/regions was displayed in Supplementary Table S2. Each node represented a different country/region. The size of the nodes is determined by the number of publications (The higher the number, the larger the node). The same color represented the same cluster. The line between the nodes represented the co-authorship between countries/regions (The stronger the cooperation relationship, the wider the line). The number of total link strengths reflected the total co-authorship strength between countries/regions.

FIGURE 2.

FIGURE 2

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Distribution of publications from different countries/regions and institutions. (A) Distribution of publications from different countries/regions (N = 23, Minimum number of publications of one country/region≥10). Data from England, Scotland, and Wales were integrated into the United Kingdom; data from Taiwan and the People’s Republic of China were integrated into China. The nodes represented countries/regions and the size of the node represents the number of publications. The lines between the nodes represent cooperation relationships and the thickness of the lines was correlated with the size of collaboration. The colors in the nodes represented the clusters. (B) Distribution of publications from different institutions (N = 30, Minimum number of publications of one institution≥27). The nodes represented institutions and the size of the node represented the number of publications. The lines between the nodes represent cooperation relationships and the thickness of the lines was correlated with the size of collaboration. The colors in the nodes represented the clusters.

As we can see from these results, there were 14 countries/regions that published only one paper and four countries/regions that published over 100 papers. Among the top 10 most prolific countries/regions (Table 2), China had the highest number of publications (1,092, 59.57%), followed by United States (489, 26.68%), Germany (151, 8.24%), and Japan (102, 5.56%). The United States had the highest number of citations (40,675), total link strength (416), and Germany had the highest number of Centrality (0.71). While Australia obtained the highest number of citations/documents (100.36) Here, high centrality (≥0.10) indicates active cooperation. Most of countries/regions cooperated with others (n = 60, total link strength≥1). The United States had the highest link strength (416), followed by China (333), Germany (226), and France (140) (Table 2). Notably, the total link strength between China and United States reached 159 (data not shown), indicating that these two countries with top publication outputs collaborated closely.

TABLE 2.

Top 10 countries contributed to publications of ferroptosis in cancer.

Rank Country Year Document Percentage (n/1833) Citation Citation/document Total link strength Centrality
1 China 2014 1,092 59.57 25,318 23.18 333 0.06
2 United States 2012 489 26.68 40,675 83.18 416 0.23
3 Germany 2014 151 8.24 14,280 94.57 226 0.71
4 Japan 2014 102 5.56 6,945 68.09 93 0.06
5 France 2013 68 3.71 5,166 75.97 140 0.33
6 Russia 2015 51 2.78 3,162 62.00 105 0.00
7 Italy 2017 51 2.78 2,789 54.69 66 0.28
8 Australia 2016 45 2.45 4,516 100.36 78 0.06
9 South Korea 2015 44 2.40 1,479 33.61 17 0.17
10 Canada 2016 40 2.18 3,382 84.55 78 0.12
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Contributions of Institutions

A total of 1737 institutions were identified that contributed to the 1833 papers. The top 10 most prolific institutions are shown in Table 3. Also, a complete list of documents, citations, and total link strength numbers of the 1833 institutions was displayed in Supplementary Table S3. As we can see, all of the top 10 institutions came from China (n = 7) and the United States (n = 3). Central South University (92, 5.02%) is the leading institute ranked by the number of publications, followed by Guangzhou Medical University (72, 3.93%) and Columbia University (67, 3.66%). Columbia University contributed the most citations (16,996) and had the highest number of citations/document (253.67). Guangzhou Medical University had the highest number of total link strengths (287) and Zhejiang University showed the highest centrality (0.24).

TABLE 3.

Top 10 institutions contributed to publications of ferroptosis in cancer.

Rank Institution (Country) Year Document Percentage (n/1833) Citation Citation/document Total link strength Centrality
1 Cent South Univ (China) 2014 92 5.02 3,617 39.32 201 0.23
2 Guangzhou Med Univ (China) 2015 72 3.93 7,029 97.63 287 0.00
3 Columbia Univ (United States) 2012 67 3.66 16,996 253.67 204 0.10
4 Univ Pittsburgh (United States) 2015 66 3.60 9,305 140.98 272 0.07
5 Shanghai Jiao Tong Univ (China) 2018 65 3.55 839 12.91 115 0.02
6 Zhejiang Univ (China) 2018 62 3.38 799 12.89 95 0.24
7 Chinese Acad Sci (China) 2017 57 3.11 2,292 40.21 177 0.23
8 Sun Yat Sen Univ (China) 2018 47 2.56 702 14.94 66 0.01
9 Fudan Univ (China) 2019 43 2.35 493 11.47 74 0.22
10 Ut Southwestern Med Ctr (United States) 2016 39 2.13 1,393 35.72 150 0.09
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The co-authorship map of the top 30 selected institutions that published at least 27 documents was visualized in Figure 2B. The map had a total of 30 terms, four clusters, 136 links, and a total link strength of 449. Each node represented a different institution. The size of the nodes was determined by the number of publications (The higher the number, the larger the node). The same color represented the same cluster. The line between the nodes represented the co-authorship between institutions (The stronger the cooperation relationship, the wider the line). The number of total link strengths reflected the total co-authorship strength between institutions. From the visualization map, we can see that there had active cooperation among these 30 institutions within and between clusters. The top three institutions with the largest total link strength among the 1833 institutions are listed as follows: Guangzhou Medical University (n = 287), University of Pittsburgh (n = 272), and Columbia University (n = 204) (Supplementary Table S3).

Contributions of Authors

A total of 10,032 authors published literature on ferroptosis with 87 authors having papers over five(Supplementary Table S4). The author visualization map was created by Citespace (Figure 3) and the top 10 authors ranked by publication frequency and centrality were shown in Table 4. In the cooperative network map (Figure 3), the nodes represented authors (the larger circle, the higher the number of publications); lines between the nodes represented a collaboration between two authors on the same article (the wider lines, the more frequency of collaborations); the colors in the nodes represented the years, and the purple ring represented high centrality (≥0.10). As shown in these data, Daolin Tang published the largest number of papers (n = 64), followed by Rui Kang (n = 58) and Brent R Stockwell (n = 48). Both Brent R Stockwell and Scott J Dixon published earliest (in 2012) and had the highest centrality (0.20).

FIGURE 3.

FIGURE 3

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CiteSpace visualization map of authors involved in ferroptosis in cancer. The nodes represent authors (the larger circle, the higher the number of publications); lines between the nodes represented a collaboration between two authors on the same article (the wider lines, the more frequency of collaborations); the colors in the nodes represented the years, and the purple ring represented high centrality (≥0.10).

TABLE 4.

The top 10 authors and co-cited authors in the field of ferroptosis in cancer.

Rank Author Count Year Centrality Co-cited author Co-citation
1 Daolin Tang 64 2015 0.04 Scott J Dixon 2,134
2 Rui Kang 58 2016 0.08 Wan Seok Yang 1722
3 Brent R Stockwell 48 2012 0.20 Brent R Stockwell 795
4 Marcus Conrad 38 2015 0.04 Minghui Gao 748
5 Jiao Liu 24 2018 0.06 Jose Pedro Friedmann Angeli 740
6 Guido Kroemer 23 2014 0.16 Sebastian, Doll 682
7 Scott J Dixon 21 2012 0.20 Le Jiang 525
8 Valerian E Kagan 20 2017 0.03 Lorenzo Galluzzi 468
9 Xin Chen 19 2020 0.03 Yangchun Xie 448
10 Hulya Bayir 18 2017 0.03 Xiaofang Sun 431
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Co-citation was defined as the frequency with which two documents were cited together by another or more papers at the same time, providing a way to study the specialty structure of science. In this study, a total of 45,521 co-cited authors were identified with 99 co-cited over 100 times (Supplementary Table S5). The co-citation density map showed the authors (n = 46) with co-citations of at least 150 and the top 10 co-cited authors were presented in Table 4. Scott J Dixon was the most frequently co-cited author (2,134 times), followed by Wan Seok Yang (1722 times) and Brent R Stockwell (795 times). It was worth noting that Scott J Dixon and Brent R Stockwell were among the top 10 productive authors and co-cited authors.

Journals and Co-Cited Journals

A total of 515 academic journals had published the 1833 papers on ferroptosis in cancer. The top 10 journals ranked by the number of publications were shown in Table 5, and a complete list of the 515 journals was displayed in Supplementary Table S6. Among the top 10 journals, Biochemical and Biophysical Research Communications (n = 54) and Frontiers in Oncology (n = 54) published the largest number of papers, followed by Frontiers in Cell and Developmental Biology (n = 52), and Cell Death & Disease (n = 51). Nine (90%) of the journals had an IF 2020 over five and seven (70%) were located in JCR (2020) Q1 region. Biochemical and Biophysical Research Communications had the largest number of total citations (1902 times). As shown in Table 6, the top three journals with the largest co-citations were Cell (co-citation: 5,342; IF 2020: 41.582), Nature (co-citation: 4,725; IF 2020: 49.962), Proceedings of The National Academy of Sciences of The United States of America (co-citation: 3,040; IF 2020: 11.205). Despite having few publications (n = 7) and a low impact factor (IF 2020: 5.157), the papers published in the Journal of Biological Chemistry obtained a large number of co-citations (2,882 times).

TABLE 5.

Top 10 journals published papers of ferroptosis research in cancer.

Rank Journal Count Citation IF (2020) JCR Category Quartile
1 Biochemical and Biophysical Research Communications 54 1902 3.575 Biochemistry & Molecular Biology (Q3); Biophysics (Q2)
2 Frontiers in Oncology 54 308 6.244 Oncology (Q2)
3 Frontiers in Cell and Developmental Biology 52 259 6.684 Cell Biology (Q2); Developmental Biology (Q1)
4 Cell Death & Disease 51 1,264 8.469 Cell Biology (Q1)
5 Redox Biology 38 1,039 11.799 Biochemistry & Molecular Biology (Q1)
6 International Journal of Molecular Sciences 36 535 5.924 Biochemistry & Molecular Biology (Q1); Chemistry, Multidisciplinary (Q2)
7 Free Radical Biology and Medicine 34 1,683 7.376 Biochemistry & Molecular Biology (Q1); Endocrinology & Metabolism (Q1)
8 Oxidative Medicine and Cellular Longevity 27 587 6.543 Cell Biology (Q2)
9 Nature Communications 26 745 14.919 Multidisciplinary Sciences (Q1)
10 Cancers 26 275 6.639 Oncology (Q1)
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TABLE 6.

Top 10 co-cited journals by papers of ferroptosis research in cancer.

Rank Co-cited journal Citation Count IF (2020) JCR Category Quartile
1 Cell 5,342 8 41.584 Biochemistry & Molecular Biology (Q1); Cell Biology (Q1)
2 Nature 4,725 11 49.962 Multidisciplinary Sciences (Q1)
3 PNAS a 3,040 13 11.205 Multidisciplinary Sciences (Q1)
4 Journal of Biological Chemistry 2,882 7 5.157 Biochemistry & Molecular Biology (Q2)
5 Cell Death and Differentiation 2,394 22 15.828 Biochemistry & Molecular Biology (Q1); Cell Biology (Q1)
6 Free Radical Biology and Medicine 2083 34 7.376 Biochemistry & Molecular Biology (Q1); Endocrinology & Metabolism (Q1)
7 Cancer Research 2019 12 12.701 Oncology (Q1)
8 Nature Chemical Biology 1783 11 15.04 Biochemistry & Molecular Biology (Q1)
9 Biochemical and Biophysical Research Communications 1,697 54 3.575 Biochemistry & Molecular Biology (Q3); Biophysics (Q2)
10 Cell Death & Disease 1,551 51 8.469 Cell Biology (Q1)
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a

PNAS: proceedings of the national academy of sciences of the United States of America.

Top Cited Publications and References Burst

A total of 20 most cited publications on ferroptosis in cancer were listed in Table 7. Of these 20 publications, fourteen were articles (70%) and six were reviews (30%). All the top 20 references were cited more than 400 times. The article (entitled Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death) published in 2012 by Dixon, Scott J et al. had the largest number of citations (3,009). The purpose of burst detection was to determine whether an entity had significantly increased its presence within a certain period(Kleinberg, 2003). Through CiteSpace analysis, the top 25 references with the strongest citation bursts were identified (Figure 4). The result showed the first burst of reference began in 2013, and the most recent reference with a citation burst was observed in 2017. Among these 25 references, six references (24%) had a duration until 2021. The reference with the strongest burstness (strength = 128.73, from 2014 to 2019) was published in Cell by Yang, Wan Seok et al., followed by the reference published in Cell by Dixon, Scott J et al. (strength = 88.88, from 2013 to 2017) and Nature Cell Biology by Angeli, Jose Pedro Friedmann et al. (strength = 84.29, from 2015 to 2019).

TABLE 7.

Top 20 ferroptosis-related publications in cancer with the most citations (up to 19 December 2021).

Rank Title Type First author Journal Year Citation
1 Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death Article Scott J Dixon Cell 2012 3,009
2 Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 Review Lorenzo Galluzzi Cell Death and Differentiation 2018 1,645
3 Regulation of Ferroptotic Cancer Cell Death by GPX4 Article Wan Seok Yang Cell 2014 1,554
4 Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease Review Brent R Stockwell Cell 2017 1,444
5 Regulated necrosis: the expanding network of non-apoptotic cell death pathways Review Tom Vanden Berghe Nature Reviews Molecular Cell Biology 2014 934
6 Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice Article Jose Pedro Friedmann Angeli Nature Cell Biology 2014 925
7 The role of iron and reactive oxygen species in cell death Review Scott J Dixon Nature Chemical Biology 2014 919
8 Ferroptosis: process and function Review Yangchun Xie Cell Death and Differentiation 2016 869
9 Ferroptosis as a p53-mediated activity during tumour suppression Article Le Jiang Nature 2015 811
10 Ferrootosis: Death by Lipid Peroxidation Review Wan Seok Yang Trends in Cell Biology 2016 724
11 ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition Article Sebastian, Doll Nature Chemical Biology 2017 681
12 Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis Article Valerian E Kagan Nature Chemical Biology 2017 581
13 Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis Article Scott J Dixon elife 2014 575
14 Glutaminolysis and Transferrin Regulate Ferroptosis Article Minghui Gao Molecular Cell 2015 558
15 Lipid peroxidation in cell death Article Michael M Gaschler Biochemical and Biophysical Research Communications 2017 513
16 Simultaneous Fenton-like Ion Delivery and Glutathione Depletion by MnO2-Based Nanoagent to Enhance Chemodynamic Therapy Article Li-Sen Lin Angewandte Chemie-International Edition 2018 510
17 Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells Article Xiaofang Sun Hepatology 2016 508
18 Autophagy promotes ferroptosis by degradation of ferritin Article Wen Hou Autophagy 2016 485
19 Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway Article Vasanthi S Viswanathan Nature 2017 479
20 Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis Article Wan Seok Yang PNAS a 2016 477
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a

PNAS: proceedings of the national academy of sciences of the United states of america.

FIGURE 4.

FIGURE 4

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Top 25 references with the strongest citation bursts involved in ferroptosis in cancer. (Sorted by the beginning year of burst.)

Analysis of Hotspots and Frontiers

To investigate the research hotspots in the field of ferroptosis in cancer, all keywords (including author keywords and keywords plus) were extracted from all the 1833 publications for Co-occurrence analysis on VOSviewer software. Table 8 shows the top 20 high-frequency keywords. Excluding “ferroptosis” (1,192 times), the most frequently appeared keywords (over 300 times) were “cell death” (434 times), “cancer” (360 times), “apoptosis” (335 times), “iron” (321 times), and “oxidative stress” (321 times). We used Citespace software to cluster the keywords and draw a timeline for keywords after clustering (Figure 5). Total 9 clusters were formed: #0 cell death; #1 prognosis; #2 drug resistance; #3 transporter; #4 photodynamic therapy; #5 mixed-lineage kinase; #6 lipid peroxidation; #7 chemistry; and #8 regulated cell death.

TABLE 8.

Top 20 keywords related to the field of ferroptosis in cancer.

Rank Keyword Occurrence Rank Keyword Occurrence
1 ferroptosis 1,192 11 cancer-cells 180
2 cell-death 434 12 Autophagy 178
3 cancer 360 13 Activation 175
4 apoptosis 335 14 Inhibition 151
5 iron 321 15 lipid-peroxidation 148
6 oxidative stress 321 16 Resistance 137
7 death 287 17 gpx4 112
8 metabolism 263 18 Cells 109
9 expression 246 19 Glutathione 100
10 mechanisms 200 20 Growth 98
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FIGURE 5.

FIGURE 5

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The timeline view of keywords. The nodes represented keywords (the larger circle, the more frequency of occurrence). Clusters’ labels were listed on the right.

To investigate the research frontiers, we used Citespace software to detect keywords burst (Figure 6). A red line indicates that the corresponding terms frequently appeared during this period, and a blue line represents relatively being used infrequently. Among the top 25 keywords with strong burst strength, “tumor suppression”, with a strength of 9.42, was ranked first, followed by “nonapoptotic cell death” (7.82) and “hepatocellular carcinoma cell” (6.18). Notably, “multidrug resistance” had a duration until 2021 and four keywords (“inhibitor”, “Alzheimer's disease”, “necrosis”, and “mitochondrial permeability transition”) had a duration not less than 5 years.

FIGURE 6.

FIGURE 6

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Top 25 keywords with the strongest citation bursts involved in ferroptosis in cancer. (Sorted by the beginning year of burst.)

Discussion

The cell is the basic unit of life. The balance between cell proliferation and cell death is therefore of critical importance for multicellular organisms, including human beings. Ferroptosis was the most recently coined form of regulated cell death, following the discovery of apoptosis (Kerr et al., 1972), necrosis (Galluzzi et al., 2017), and pyroptosis (Galluzzi et al., 2018; Hu et al., 2021). In the past 10 years, multiple roles of ferroptosis in health and disease have been confirmed (Dixon and Stockwell, 2019;Han et al., 2020;Li et al., 2020;van Swelm et al., 2020;Chen et al., 2021c;Zhang et al., 2021b). The number of publications related to ferroptosis was growing exponentially, especially in the field of cancer research (Figure 1; Table 1) (Chen et al., 2021b; Jiang et al., 2021). As a rapidly evolving research area, it was of great challenge to gain a systematic understanding of developments, especially for those who are new to this field. To get a better understanding of the research trends in the field of ferroptosis in cancer, we conducted this study.

Previously, several bibliometric analysis studies had been conducted on ferroptosis (Zhang J. et al., 2021; Wu et al., 2021; Xiong et al., 2021). However, all these studies were set to a timeline limited to 2020 and no bibliometric studies have provided a global landscape of the ferroptosis research in cancer. In this study, a total of 1833 publications on ferroptosis in cancer were identified in the Web of Science Core Collection database from 2012 to 2021. To our surprise, more than 800 publications have been produced in 2021, accounting for almost half of all publications produced over the last 10 years. Previously, several studies have been conducted on bibliometric analysis of ferroptosis in all fields, including 1,285 publications (Wu et al., 2021), 1,363 publications (Xiong et al., 2021), and 1,267 publications (Zhang J. et al., 2021), respectively, with the timeline limited to 2020. To our best knowledge, the current study was the first comprehensive bibliometric study conducted on ferroptosis in the field of cancer research.

Generally, the number of publications in a research area can reflect productivity (Durieux and Gevenois, 2010), and the number of citations was used to represent the impact (Muniz et al., 2018). They are two main bibliometric indicators to evaluate the level of research (Seglen, 1997). Based on the observed (Figure 1) and predicted (Supplementary Figure S2) trends of publications and citations from 2012 to 2021, we can pronounce that the field of ferroptosis in cancer has entered a rapid growth period. More than 60 countries/regions had published papers on ferroptosis (Supplementary Table S2), indicating that the research on ferroptosis in cancer has attracted attention from all over the world. China and United States had the most publications and citations, respectively (Table 2). This indicated that Chinese researchers are of great interest in the research of ferroptosis in cancer and United States was in a dominant position in this field. Interestingly, the top 4 countries (China, United States, Germany, and Japan) with the highest number of publications (Table 2) were also the top 4 countries ranked by gross domestic product (GDP) (https://datacatalog.worldbank.org/dataset/gdp-ranking, accessed on 16 November 2021). This suggested that economic development may affect academic research, especially for an active field like ferroptosis in cancer.

Throughout the 10 years, Biochemical and Biophysical Research Communications (n = 54) and Frontiers in Oncology (n = 54) published the highest number of manuscripts in the field of ferroptosis in cancer (Table 5). Despite having a relatively low impact (located in the JCR Q2 region), these two journals made a notable contribution to the development of ferroptosis in cancer research. Among the top 10 most cited publications (Dixon et al., 2012; Angeli et al., 2014; Dixon and Stockwell, 2014; Vanden Berghe et al., 2014; Yang et al., 2014; Jiang et al., 2015; Xie et al., 2016; Yang and Stockwell, 2016; Stockwell et al., 2017; Galluzzi et al., 2018), six were reviews, indicating the important role of this type of literature. As listed in Table 7, the top 20 articles are considered fundamental to ferroptosis in cancer research. We suggested reading these papers to get an in-depth knowledge of the field. Based on the publications collected in this study, we summarized all the currently known cancer types associated with ferroptosis in Figure 7.

FIGURE 7.

FIGURE 7

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Diseases related to ferroptosis in various human body systems (created with https://biorender.com/).

Although ferroptosis contributed to a plethora of human diseases, the roles of ferroptosis in cancer have been by far the most extensively studied. Overall, cancer cells have been shown to have a more active metabolism, higher reactive oxygen species load, and higher iron demand than normal cells (Hassannia et al., 2019; Jiang et al., 2021). These characteristics rendered the ferroptosis pathway a promising target for cancer treatment. In addition, recent discoveries indicated that perturbation in several cancer-related pathways (such as RAS, TP53, NFE2L2, autophagy, and hypoxia) is linked to an acquired sensitivity to ferroptosis (Chen et al., 2021b). Currently, a list of clinical trials of potential ferroptosis inducers in oncology is ongoing, including SLC7A11 inhibitors (Sorafenib and Sulfasalazine), GPX4 inhibitors (Altretamine and Withaferin A), and iron activators (Neratinib, Salinomycin, Lapatinib) (Chen et al., 2021b). The combination of proferroptotic drugs with other anticancer therapies (such as immunotherapy or radiotherapy) may be a potential strategy to overcome resistance to traditional cancer therapies.

Multidrug resistance was defined as a complex phenotype characterized by developing resistance to a broad range of structurally unrelated anticancer drugs (Gottesman, 2002). It was a significant biomedical and clinical problem leading to treatment failure in cancer (Assaraf et al., 2019). The most common underlying mechanism of multidrug resistance was the role of ATP-binding cassette (ABC) transporters in drug efflux from cancer cells. Recently, Cao et al. showed that disruption of the ABC-family transporter multidrug resistance protein 1 (MRP1) prevents glutathione efflux from the cell and strongly inhibits ferroptosis, highlighting the role of ferroptosis in overcoming cancer multidrug resistance (Cao et al., 2019). Furthermore, other groups also provided evidence that triggering ferroptosis with compounds shows great potential in cancer therapy by bypassing the multidrug resistance effect (Mbaveng et al., 2018; Gao et al., 2019; Zhou et al., 2019; Du et al., 2021). Nanoparticle drug delivery, chemical optoepigenomics, and polymeric photothermal agents were emerging tools of great advantage in ferroptosis therapy to overcome multidrug resistance (Shi et al., 2018; Zhang X. K. et al., 2021; Fu et al., 2021). Of note, in the present study, the top three largest clusters were labeled “cell death, “prognosis”, and “drug-resistance” in the clustering analysis of keywords (Figure 5), and “multidrug resistance” were the only keyword that had duration until 2021 (Figure 6). Together, these results suggested that future research on novel strategies to overcome drug or multidrug resistance may be the frontier in the field of ferroptosis in cancer.

The present study was not without limitations. Firstly, this study queried only the Web of Science Core Collection database. High-quality papers published in journals that are not included in the Web of Science Core Collection database may be missed. The combination of Web of Science with other databases, such as PubMed, Google Scholar, and Scopus, would enable a more robust bibliometric analysis. Secondly, this study also comes with certain limitations inherent in CiteSpace and VOSviewer software. For instance, some keywords in the papers maybe not be included in the analysis due to the incomplete keyword extraction method and the clustering analysis based on only the main information (not the full text). Thirdly, authors, institutions, or keywords may have different expression types, bias may exist.

Conclusion

Overall, the bibliometric analysis of this study offers comprehensive information about the publication performance of ferroptosis in cancer. Our results showed that research on ferroptosis is flourishing in the field of cancer. Ferroptosis has aroused great interest in the community of cancer research all over the world. Although in its infancy, triggering ferroptosis holds great potential for the development of cancer treatment, especially for overcoming multidrug resistance. Future research on novel strategies to overcome drug or multidrug resistance may be the frontier in the field of ferroptosis in cancer.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Author Contributions

GL and TX conceived the study. GL collected the data. TX and HY re-examined the data. GL and TX analyzed the data and wrote the manuscript. WZ and YL reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.

Funding

This project was supported by the Hunan Clinical Research Center for Chronic Kidney Disease (No. 2019SK4009), the Hunan Province Office of Education (No. 21B0052), the Scientific Research Projects of the Health Commission of Hunan Province (No. 202203050006), the National Natural Science Foundation of China (No. 82100788), the Fellowship of China Postdoctoral Science Foundation for Innovative Talents (No. BX2021382), and the Fellowship of China Postdoctoral Science Foundation (No. 2021M693571).

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.

The reviewer KX declared a shared affiliation with the authors HY, WZ, and TX to the handling editor at the time of review.

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.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcell.2022.841724/full#supplementary-material

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Supplementary Materials

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Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

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