Emerging trends and research hotspots in the relationship between mast cells and atopic dermatitis based on the literature from 2001 to 2024: A bibliometric and visualized analysis

Abstract

Background

Atopic dermatitis (AD) is a prevalent chronic inflammatory and highly pruritic skin condition characterized by the infiltration of immune cells, notably eosinophils and mast cells. Mast cells (MCs) critically participate in the complex pathogenesis of AD through multiple pathways and have recently garnered growing attention in research. Despite the abundance of related studies published over the years, a comprehensive bibliometric analysis on this topic remains lacking.

Objective

Our objective was to perform an up‐to‐date bibliometric analysis of the literature focusing on the relationship between MCs and AD. This analysis would provide valuable insights through a thorough bibliometric review, enabling a clearer understanding of the current research landscape, pinpointing key studies, and detecting emerging trends within this field.

Methods

We searched the Web of Science Core Collection (WoSCC) database on 15 July 2024. The data retrieval strategy was structured as follows: #1: TS = (“mast cells”) OR TS = (“mast cell”) OR TS = (“mastocyte”); #2: TS = (“atopic dermatitis”) OR TS = (“atopic eczema”) Final data: (#1 AND #2). A total of 2272 items published between 2001 and 2024 were included. Several scientometric visualization tools, including VOSviewer, R‐bibliometrix, CiteSpace and an online analytical platform, were utilized to conduct text mining and to visualize the bibliometric data, facilitating a comprehensive analysis of research trends and patterns.

Results

Out of the initial 2272 articles retrieved, 2168 were selected for analysis after applying inclusion and exclusion criteria based on publication type. The findings indicate a steady and substantial exponential growth in the annual number of publications focused on the relationship between over the years. The South Korea (547/2168), USA (465/2168) and Japan (436/2168) were the major contributors within this field, collectively constituting more than half of the total publications. To clarify the underlying mechanisms and role of MCs in the pathogenesis of AD and to make MCs prime targets for therapeutic intervention have garnered the most attention in this field. According to references analysis, the research emphasis has shifted to developing MC‐related therapeutics and intervention and regulating the immune system of AD patients through modulating the activity of various immune cells. On the basis of keywords analysis, we outlined the following research frontiers and hotpots in the future: the role of oxidative stress in the pathogenesis; imbalance in the different types of T helper (Th) cells during immune response; skin barrier and barrier dysfunction; improving quality of life; sensory neurons; biological agents and small‐molecule drugs. Furthermore, IL‐13, IL‐4, NFKB1, BCGF‐1 and CD4 ranked as the top five genes that have received the most investigative attention in the intersection of MCs and AD.

Conclusion

In a word, this analysis would greatly benefit from a thorough bibliometric review to gain a deeper understanding of the current research landscape, identify pivotal studies and pinpoint emerging trends in the field of MCs and AD. Meanwhile, our findings offered researchers a holistic perspective of ongoing developments, serving as a valuable resource for guiding future research and informing decision‐making for both researchers and policymakers in this area.

1. INTRODUCTION

Atopic dermatitis (AD) is a common chronic relapsing inflammatory skin disease, and severe itching and recurrent eczema‐like skin lesions, ¹ desquamation and even lichen‐like skin changes are the main clinical features. Incidences of AD have been increasing annually, ² which has brought a great burden a great burden to human health undertakings and social development. ³ The pathogenesis of AD is complex, involving genetic backgrounds, environmental factors, skin barrier destruction and aberrant autoimmune responses. ⁴ Mast cells (MCs), as a diverse and ubiquitously distributed immune cells, mediate the occurrence of a range of allergic disorders. ⁵ MCs originate from pluripotent hematopoietic stem cells within the bone marrow. They circulate through the bloodstream and lymphatic system before undergoing differentiation and maturation within a specific immune micro‐environment. ⁶ Based on their phenotype and function, they can be classified into two main subtypes: mucosal mast cells (MMCs) and connective tissue‐type mast cells (CTMCs), and skin‐derived MCs have many characteristic features of CTMC. ⁷ In the process of AD, MCs can respond to the stimulation of various common AD predisposing factors, such as allergens, self‐antigens, bacterial/fungal‐derived antigen components, neuropeptides and physical stimulation. ⁸ Upon activation, MCs release a wide array of inflammatory mediators, including histamine and tryptase, which plays a key role in generating the hallmark pruritus associated with AD. ⁹

In recent years, the potential underlying mechanisms of MCs in AD have been widely investigated. Nevertheless, several issues remain to be further addressed. First, in addition to the traditional classification, the typing basis of MCs has become more complicated with advancements in research over recent years. Accordingly, the regulatory mechanisms of different classifications of MCs at different stages remain to be thoroughly explored and warrant further in‐depth investigation, ⁵ as different MCs types play distinct roles in the pathogenesis. Second, there are no clinically approved drugs specifically targeting MCs for the treatment of AD to date. Although existing medications and their impact on other factors/cells may potentially downregulate the number or activation of MCs, the way for clinical for MCs‐targeted therapies is still long and curvy. ¹⁰ Third, many inflammatory mediators are released following the activation of MCs. However, the endogenous modulators involved in MCs activation and their potential mechanisms remain to be elucidated. ¹¹ Thus, how to accurately regulate the activity of MCs still remains open. Given these facts, the role of MCs in AD has garnered growing attention, leading to a recent surge in related research publications. However, a comprehensive study objectively summarizing or analyzing emerging trends in this domain has yet to be conducted. Additionally, with the overwhelming amount of information, scholars must invest significant time reviewing academic literature to remain informed about recent developments in their field. Although systematic reviews and meta‐analyses have important value in summarizing and evaluating available evidence, the depth and quality of existing articles and summaries are constrained by multiple biases and the limited expertise of individual researchers, resulting in analyses that are often fragmented and narrow in scope. It is noteworthy that bibliometric analysis could address these shortcomings. ¹² As a scientific evaluation method, bibliometric analysis can provide certain critical insights that systematic reviews may not capture.

Bibliometrics is a discipline that employs mathematical and statistical techniques to quantitatively and qualitatively analyze the structure, distribution and developmental trajectories of academic publications, ¹³ providing an impartial and thorough overview of the present research landscape, development patterns and research frontiers and trends. ¹⁴ This technique also holds immense significance in aiding in comparing contributions across various dimensions, including countries nations, institutions, journals, authors and funding agencies, providing valuable insights into the global research landscape. ¹⁵ , ¹⁶ As more and more software tools such as CiteSpace ¹⁷ , VOSviewer ¹⁸ and R‐Bibliometrix package ¹⁹ are used for bibliometric analysis from multiple dimensions, this methodology is broadly utilized across medical fields. ²⁰ In recent years, the application of bibliometrics in dermatology has gained increasing prominence, not only for its ability to highlight emerging research focuses and developmental trends in areas like psoriasis, ²¹ cutaneous tumors ²² , cellulitis of the scalp ²³ and urticaria. ²⁴ Bibliometric analysis also serves as a valuable tool for assessing the impact and evidence quality of clinical and practice guidelines in dermatology by evaluating the citation quantity and quality within these guidelines, thereby offering guidance for clinical decision‐making. Furthermore, this method can identify research gaps and weaknesses within dermatology, enabling researchers to systematically uncover underexplored areas and propose innovative directions for future investigations. Take AD as an example, Zhang ²⁵ and his colleagues have collected 37 937 documents related to AD and the top 100 most cited articles were identified and analyzed by using bibliometric approach. In this article, they highlighted that research has focused on elucidating the pathogenesis of AD over the past 20 years, with significant attention given to the functional loss of the epidermal barrier protein filaggrin, which plays a crucial role in maintaining skin barrier integrity. ²⁶ Subsequently, attention has shifted toward the introduction of biologics and Janus kinase (JAK) inhibitors as innovative treatment options, notably dupilumab, ²⁷ emerging as pivotal research focus within treatment strategies of AD. ²⁸ In line with this, several bibliometric studies have also investigated various aspects related to AD treatment. These studies explored ocular adverse effects during treatment of dupilumab, ²⁹ the role of IgE, ³⁰ skin/intestinal microbiome, ³¹ probiotcs, as well as the involvement of immune cells in the inflammatory response, particularly Th2 and Th17 cells, along with related cytokines such as IL‐25, IL‐31, IL‐33 and thymic stromal lymphopoietin (TSLP) in AD. However, from our literature search, there has yet to be a bibliometric analysis specifically addressing global research trends in the field of MCs and AD.

Consequently, to bridge this existing void, the present study employs a bibliometric approach, utilizing the authoritative Web of Science Core Collection (WoSCC) database to gather relevant publications concerning MCs and AD from 2001 onwards. In this project, we primarily conducted our analysis by employing bibliometrics, examining worldwide patterns in publication and summarizing the growth of published articles, nations, institutions, authors, research hotspots and the most studied genes in this domain. In a word, our desire is to obtain an objective and thorough understanding of the role of MCs in AD, identify key publication metrics and collaboration patterns, divulge evolving research trends and emerging frontiers, offer valuable data support for research management and decision‐making by utilizing bibliometric analysis.

2. MATERIALS AND METHODS

2.1. Data source and retrieval strategy

On July 16, 2024, the study was carried out by two independent authors to conduct a comprehensive search for publications related to MCs and AD spanning 2001−2024 to avoid bias. Based on the previous studies, ³² we ultimately selected the Web of Science Core Collection (WoSCC) database for our bibliometric analysis after weighing the pros and cons. The WoSCC database managed by Clarivate Analytics (USA)is highly regarded as a premier citation database for scientific research, as many scholars considered that it is the most appropriate resource for bibliometric analysis due to its comprehensive coverage and precise citation tracking. ³³ An advanced retrieval strategy was implemented with the following parameters: #1: TS = (“mast cells”) OR TS = (“mast cell”) OR TS = (“mastocyte”); #2: TS = (“atopic dermatitis”) OR TS = (“atopic eczema”). Final data: (#1 AND #2). Subsequently, the inclusion criteria specified that only English‐language documents published from January 1, 2001, to July 15, 2024, were considered. The selection criteria were restricted to review and research articles, excluding meeting abstracts, editorials, and letters. A detailed outline of the retrieval strategy and screening process is presented in Figure 1.

FIGURE 1.

Data source and retrieval strategy. Flowchart of detailed retrieval strategy and literature selection and screening process.

2.2. Data collection and preliminary analysis

Based on the final analysis, data collection was performed on all retrieved literature. Precisely, all data were downloaded in “Full Record and Cited References” format, exported as plain text, and analyzed to extract bibliometric indicators, including annual publication and citation counts, as well as key contributors such as regions, authors and funding agencies. To the best of our knowledge, there are some inevitable defects of WOSCC that necessitate manual inspection and correction. Therefore, we need to perform a preliminary analysis of the data. To cite an example, publications from Taiwan should be categorized under China and the documents from Northern Ireland, Wales, England and Scotland should be assigned to the United Kingdom. ³⁴ Additionally, journal information such as impact factors (IF) and subject category quartile rankings (Q1/Q2/Q3/Q4) were obtained from the Journal Citation Reports.

2.3. Bibliometric analysis and statistical analysis

For advanced bibliometric analysis and data visualization, we utilized three open‐source tools: CiteSpace software (version 6.3R1), VOSviewer software (version 1.6.20) and the R‐Bibliometrix package. CiteSpace ³⁵ was developed by Dr. Chaomei Chen (2004), is a visualization tool that leverages the Java programming language to analyze and visualize citation networks. It is designed to help researchers and scholars explore the intellectual landscape of a particular field, identify key contributors and uncover emerging trends. VOSviewer, developed in 2009 by the Scientific and Technological Research Centre of Leiden University, is another powerful tool designed for constructing and visualizing bibliometric networks. ¹⁸ This software enables the construction of these networks based on citation relationships, bibliographic coupling, journals co‐citation, cooccurrence of keywords or co‐authorship connections. Bibliometrix R‐package software ³⁶ was used for conducting quantitative analysis in our study; it is an open‐source software that enables users to conduct bibliometric analyses without requiring coding skills. In addition, we collected gene‐related data for MCs and AD from the online resource (https://www.citexs.com/Summary) and conducted gene interaction network and functional enrichment analysis by using Search Tool for the Retrieval of Interacting Genes (STRING) database(https://string‐db.org/) ³⁷ .In these visualization maps, the node size corresponds to frequency and the node highlighted with a purple outer ring suggests significant hotspots or key transformative points in the field. The line thickness denotes the strength of connections with the number of lines indicating the degree of collaboration. As for cluster map, there are two important evaluation indicators, namely modularity Q (Q value) and mean silhouette (S value). The Q value measures the coherence of clustering and network structure, with a value greater than 0.3 signifying a significant clustering structure. The S‐value assesses the quality of clustering, with a value above 0.7 signifying robust clustering outcomes. ³⁸ Furthermore, the annually publication and citation counts were summarized with descriptive statistics.

3. RESULTS

3.1. Statistical analysis of annual publications and citation frequency

A total of 2168 papers were included in the study, comprising 1703 original articles and 465 reviews. By the search date, these publications had been cited 84 458 times, with an average of 38.96 citations per article.

Figure 2 illustrates the annual volume of publications and citation frequencies from 2001 to 2024. The average annual growth rate over this period, from 2001 to 2023, was calculated to be 23.1%, calculated using the following formula: annual growth rate = 

$${\left[\frac{\mathrm{number}\mathrm{of}\mathrm{papers}\mathrm{in}\mathrm{the}\mathrm{last}\mathrm{year}}{\mathrm{number}\mathrm{of}\mathrm{papers}\mathrm{in}\mathrm{the}\mathrm{first}\mathrm{year}}\right]}^{\frac{1}{\mathrm{last}\mathrm{year}-\mathrm{first}\mathrm{year}}}-1$$

FIGURE 2.

The annual volume of publications and citation frequencies. The number of publication and citation frequency from 2001 to 2023 is shown in the main plot. The graph in the upper left shows the fitted curve of annual publication from 2001 to 2023, and the equation Y = 43.424e0.0551X (R2 = 0.936, X was the year, Y was the annual outputs).

The fitted curve indicates an exponential growth in annual publications during this period, described by the equation Y = 43.424e0.0551X (R ² = 0.936), where X represents the year and Y represents the annual output. Similarly, the annual citation count also follows an exponential growth trend (R ² = 0.9356). A statistically significant linear correlation was observed between the number of citations and publications, with a robust correlation coefficient (r = 0.9734) calculated by Pearson's correlation coefficient test. In summary, this trend reflects growing academic and clinical interest in understanding the complex interactions between these immune cells and chronic inflammatory skin conditions. The surge in research output also underscores the expanding recognition of MCs as potential therapeutic targets, driving advancements in both basic and translational studies within the field.

3.2. Analysis of main contributors and cooperative network

3.2.1. Countries/regions

Based on statistics, literature related to MCs and AD has been published by researchers from 65 countries/regions. We analyzed the number of articles published by each country to assess their participation in this field. As shown in Figure 3A,B, we can see from the world map that the three countries with the highest number of published articles are shaded the darkest; in addition, Figure 3B displays the specific values, as South Korea, the United States and Japan rank in the top three, each publishing over 400 papers. In Figure 3C, the stacked bar chart visually represents the annual number of published studies from the top 10 countries/regions between 2001 and 2024. Figure 3D,E depict multinational collaborations between various countries/regions. The width of the connecting lines between nodes symbolizes the strength of these partnerships, with thicker lines denoting stronger cooperative relationships. Robust collaborations between the USA and South Korea, China and Japan could be observed. Additionally, the color of the nodes can represent the average appearance year (AAY) and generally more vibrant colored nodes indicate that the country has more recently engaged in this field.

FIGURE 3.

Analysis of countries/regions of publications. (A) The world map of countries/regions in this field. (B) The top 10 most prolific countries/regions. (C) The stacked bar chart of annual published studies of top 10 countries/regions from 2000 to 2024. (D) Multinational cooperations between different countries/regions. (E) Visualization map of multinational co‐authorship analysis generated by VOSviewer.

3.2.2. Institutions and funding agencies

Figure 4A shows the institutional collaboration network map generated by CiteSpace. In this visualization, the size of the nodes represents the number of publications from the corresponding institutions. Moreover, nodes with a purple outer ring indicate high centrality, identifiable by a BC value exceeding 0.1. Figure 4B presents a summary of the top 10 most prolific institutions, ranked by the number of publications, Kyung Hee University had the most publications, followed by Free University of Berlin and Charite Universitatsmedizin Berlin. Additionally, the top 10 institutions based on the BC values is shown in Figure 4C. It can be seen that Harvard University (BC = 0.51) ranks first with the highest centrality values. Figure 4D shows the top eight funding agencies. Notably, four of these agencies are from the United States. The United States Department of Health and Human Services (HHS) ranks first, supporting the highest number of publications at 209 papers. The National Institutes of Health (NIH) in Japan sponsored 206 studies, securing the second position, while the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) in Japan and the National Research Foundation of Korea (NRF) both rank third, each funding 156 papers.

FIGURE 4.

Analysis of institutions and funding agencies of publications. (A) The cooperation visualization map generated by CiteSpace. (B) The top 10 most prolific institutions. (C) The top 10 institutions based on the BC values. (D) The top eight funding agencies.

3.2.3. Authorship and co‐cited authors

A total of over 10 000 authors contributed to these 2168 studies. The frequency of article publication reflects the level of academic activity and the contribution to their research fields. Figure 5A indicates that Kim, HM, with 35 publications, is the most prolific author, followed by Jeong, HJ (27 publications) and Kim, SJ (24 publications). In addition, analyzing the relationships between authors and their co‐authors provides insights into existing collaborations, which can foster further communication and the development of potential collaborative projects. Figure 5B, generated by VOSviewer, illustrates eight distinct research clusters, highlighting close collaborations between different groups of authors.

FIGURE 5.

Analysis of authorship and co‐cited authors of publications. (A) The top 10 prolific authors in this field. (B) A visualization map depicting author co‐authorship clusters generated by VOSviewer. A total of eight distinct clusters have been marked on the map. (C) Network visualization map of author co‐citation analysis with more than 50 citations. (D) The top 10 authors with the highest TLS.

Out of 44 937 co‐cited authors, 12 have been co‐cited more than 200 times. Leung DYM is the most frequently co‐cited author with 777 citations, followed by Galli SJ (n = 500) and Theoharides TC (n = 470). Figure 5C displays the co‐citation network, focusing on authors co‐cited at least 50 times. Each node represents an author, with node size proportional to their citation frequency. Significantly, frequently cited authors exhibit dynamic collaborations, depicted by nodes of the same color within the network. Total link strength (TLS) is used to evaluate their positions within cooperative and co‐citation relationships. Figure 5D presents the top 10 authors based on TLS, with Theoharides TC, Slominski A and Leung DYM leading the list. Furthermore, using CiteSpace to analyze mutual collaborations among authors confirmed the consistency of these findings.

3.3. Analysis of noteworthy journals and research areas

Publications in this domain are distributed across 534 journals. Based on publication counts, the Journal of Allergy and Clinical Immunology had published the highest number of studies with 102 articles, followed by the International Journal of Molecular Sciences (n = 70) and Journal of Investigative Dermatology (n = 69). According to the latest Journal Citation Reports, most of these journals are classified in Q1/Q2 categories, with Allergy having the highest IF of 12.6. Notably, half of these journals' publishers are from the United States. Figure 6A illustrates the network visualization of 182 journals with over 100 co‐citations, highlighting that the Journal of Allergy and Clinical Immunology has been cited over 10 000 times. The journals with the highest TLS are the Journal of Allergy and Clinical Immunology, the Journal of Immunology, and the Journal of Investigative Dermatology. The WoSCC database categorizes these documents into various research fields. Figure 6B shows the top 10 research fields by publication count, indicating a primary focus on Immunology and Pharmacology. This emphasis likely correlates with studies on the pathogenesis and treatment of AD. Figure 6C illustrates a dual‐map overlay depicting clusters of citing and cited journals. The map delineates three primary citation pathways: two are represented in orange and one in green.

FIGURE 6.

Analysis of noteworthy journals and research areas. (A) Network map of 182 co‐cited journals with more than 100 citation times. (B) The top 10 research domains organized by their respective publication counts. (C) A dual‐map overlay depicting the journals in this domain. The map reveals three primary citation paths including two orange paths and one green path.

3.4. Analysis of highly cited studies and co‐citation references

Figure 7A illustrates the network visualization of citation analysis for 2168 included papers, with node size representing citation frequency and node color indicating publication year. This visualization clearly depicts the relative citation impact of each study, highlighting significantly cited works. Notably, the paper by Galli et al. (2008) garnered 1342 citations, providing a comprehensive review of advances in allergic disease research and future perspectives on targeting inflammatory mediators and immune cells, emphasizing the role of MCs in AD pathogenesis and treatment. The study by Liew et al. ranked second with 819 citations, followed by Eichenfield et al. with 803 citations.

FIGURE 7.

Analysis of highly cited studies and co‐citation references. (A) The network visualization map for document citation analysis. (B)The network visualization map of reference co‐citation analysis constructed based on CiteSpace. (C) A timeline view network map of co‐cited references. The utilization of the clustering function resulted in the division of the network map into distinct clusters. (D) The top 10 references with citation bursts. The red segment corresponds to the initiation and end years of the burst duration.

Co‐citation analysis evaluates the relationships between co‐cited papers, identifying authoritative research and key contributors. Figure 7B, generated by using CiteSpace, shows the network visualization of co‐cited references, with a Q value of 0.8084 and an average S value of 0.9224. Highly central references include Bieber et al. (2008, centrality = 0.46), Kim et al. (2013, centrality = 0.43), and Leung et al. (2003, centrality = 0.36). Subsequently, the clustering analysis using the software revealed that all co‐cited references could be categorized into nine distinct groups. Figure 7C presents the timeline view of these clusters: Thymic Stromal Lymphopoietin (0), New Insights (1), Nga Mice (2), Abnormal Skin Barrier (3), Signal Transducers (4), Long‐term Efficacy (5), Tetramethoxybenzene Inhibits House Dust Mite (6), Novel Therapies (7), Itch Related to Inflammation (8) and Brain‐Skin Connection (9). Cluster #0, the largest with 23 members, centers on a review article discussing advances in AD pathophysiology and management strategies. In this timeline view, clusters positioned toward the right end of the axis highlight recent research topics, as can be seen that recent research focuses on clusters #1 (New Insights), #4 (Signal Transducers) and #7 (Novel Therapies), indicating a continued emphasis on innovative treatments for AD. Figure 7D summarizes the top 10 documents with the strongest citation bursts, providing a comprehensive reference for future research directions.

3.5. Analysis of keywords co‐occurrence and burst keywords

Keyword co‐occurrence analysis effectively reveals the popular hotspots in the field. First, we analyzed the annual trend of the top 15 keywords (Figure 8A). Subsequently, we extracted keywords appearing more than 15 times from the dataset of 2168 publications, manually removed irrelevant terms, merged synonymous keywords and analyzed them using VOSviewer. Figure 8B shows the overlay visualization, with node size representing occurrence frequency and a heat map indicating temporal changes. Figure 8C presents the item density map for keyword co‐occurrence analysis, where strong fluorescent shades denote active research areas with high keyword frequency, and pale blue shades indicate less active areas. Additionally, we used CiteSpace to identify the top 40 keywords with the strongest citation bursts (Figure 8D).

FIGURE 8.

Analysis of keywords co‐occurrence and burst keywords. (A) The annual change trend of the top 15 related keywords in this domain. (B) overlay visualization, with node size representing occurrence frequency and a heat map indicating temporal changes. (C) Item density map for keyword co‐occurrence analysis, where strong fluorescent shades denote active research areas with high keyword frequency, and pale blue shades indicate less active areas. (D) The The top 40 keywords with the strongest citation explosion.

3.6. Analysis of hot spot genes

We generated a list of the most extensively studied genes in the fields of MCs and AD using an online data analysis platform. As illustrated in Figure 9A, IL‐13, IL‐4, NFKB‐1, BCGF and CD4 are the top five genes that receive the most attention at the intersection of MCs and AD. To investigate the molecular mechanisms underlying these genes, we used the STRING tool to construct a gene interaction network (Figure 9B). Simultaneously, we performed Gene Ontology (GO) enrichment analysis on the top 15 related genes, which is displayed in a bubble chart. As shown in Figure 9C, the analysis reveals that these genes are primarily involved in regulating inflammatory responses, leukocyte activation, cytokine production and cell activation, highlighting their roles in immune modulation and inflammation.

FIGURE 9.

Analysis of hot spot genes. (A) The top 15 most studied genes in the intersection of MCs and AD. (B) The gene‐interacting network by using STRING tool. (C) The bubble chart showing the GO enrichment analyses of these top related genes.

4. DISCUSSION

Atopic dermatitis is a chronic, inflammatory skin condition characterized by recurrent flare‐ups and the infiltration of various immune cells, including MCs and eosinophils ³⁹ .

Despite extensive research, the pathogenesis of AD remains incompletely understood. MCs play a crucial role in many allergic diseases, yet their specific contribution to AD pathogenesis is not fully clear. Researchers have observed a significant increase in MC numbers within AD lesions. ⁴⁰ Additionally, repeated exposure to house dust mite antigen and staphylococcal enterotoxin B can induce AD in mouse models. However, Kit‐/‐ mice and Kit‐dependent MC‐deficient mice do not respond to these stimuli. ⁴¹ Over the past few decades, intensive research efforts have elucidated the role of MCs in AD, leading to significant advancements in the management of allergic conditions like AD.

Therefore, we conducted a comprehensive scientific review of relevant publications of MCs and AD, potentially offering new perspectives for the treatment and research of AD.

4.1. Analysis of main research findings based on bibliometric analysis

This study investigates the global trends and research hot spots in related publications over the past two decades using bibliometric analysis. Unlike meta‐analyses, bibliometric studies employ more lenient screening criteria, enabling the inclusion of a larger dataset, which leads to more objective and comprehensive results. To the best of our knowledge, this is the first bibliometric analysis aimed at clarifying the structural associations and temporal trends in research in MCs research related to AD. We retrieved and screened a total of 2168 relevant publications from the WOSSC. Collectively, our results demonstrated a fluctuating yet predominantly exponential growth in publications over the years, reflecting the increasing attention in this research area and its emergence as a significant research hotspot. Notably, the annual citation frequency fluctuates in parallel with the annual publication count. A key factor contributing to the increase in publications is the rising incidence of AD in recent years. The persistent recurrence and complications, coupled with the lack of effective treatments, have imposed a significant burden on public health. ⁴²

Among the 65 countries/regions that have published related papers in this field, South Korea, the United States and Japan rank as the top three, each with over 400 publications. It is shown that, over the past two decades, the United States and Japan have consistently been leading contributors, while South Korea has experienced a dramatic increase in publication volume since 2011 and has developed strong international collaborations, gradually establishing itself as a dominant player in this field. Several factors contribute to this trend. First, South Korea's medical and beauty industries place a high priority on skin health, making dermatology a key research area, with AD being a major focus due to its prevalence. Second, South Korean research institutions engage frequently in international academic exchanges, enabling them to rapidly assimilate and apply the latest research findings, which has significantly advanced their AD research. Third, South Korea boasts several internationally renowned universities and research institutions in dermatology, such as Seoul National University and Yonsei University, whose researchers have published numerous high‐impact papers in the field of AD. The data presented in Figure 4A,B reinforce these findings, showing that six of the 10 institutions with the highest publication volumes are based in South Korea.

Academic journals play a vital role in the dissemination of knowledge and the advancement of scientific research. ⁴³ The number and quality of published papers are key criteria for assessing the academic standing of researchers. Additionally, the impact factor (IF) of academic journals serves as a critical metric for gauging a journal's influence and the quality of its published papers. Based on the analysis of publication numbers, the Journal of Allergy and Clinical Immunology, the International Journal of Molecular Sciences, and the Journal of Investigative Dermatology are the top three journals with the highest number of publications in this field. These journals play a critical role in disseminating research related to MCs and AD. However, evaluating journal quality solely by the number of publications is insufficient. ⁴⁴ The IF of a journal, calculated based on the citations its articles receive, is a crucial metric for assessing its influence. Co‐citation analysis reveals that the Journal of Allergy and Clinical Immunology, the Journal of Immunology and the Journal of Investigative Dermatology have the highest TLS, underscoring their significant impact in this field by publishing numerous innovative and influential articles. Figure 6C presents a journal dual‐map overlay, depicting citation relationships and knowledge flow between disciplines through two maps (one for citing journals and one for cited journals. ⁴⁵ This visual representation helps understand the overall structure and development trends in academic research. The map highlights three main citation pathways: two in orange and one in green. Our results indicate that publications in molecular/biology/genetics and health/nursing/medicine are frequently cited by those in medicine/clinical/medicine and molecular/ biology/immunology. Therefore, fostering strong interdisciplinary connections is a means to support and advance research in this field. Additionally, the WoSCC database could categorize these documents into various research fields. Figure 6B displays the top 10 research domains ranked by the number of publications in each area. Among the most studied fields are Immunology, Pharmacology Pharmacy and Dermatology. Analysis of journals with high publication numbers reveals that research on the pathogenesis and treatment of AD remains a key focus. This includes significant interest in biological agents and small molecule drugs targeting inflammatory mediators and immune cells. Although there are currently no clinical drugs specifically targeting MCs for AD, existing drugs and their interactions with other cells or factors may influence MCs numbers or activity. Currently, the anti‐KIT monoclonal antibody Barzolvolimab (CDX‐0159) ⁴⁶ is undergoing active clinical trials. Researchers believe that Barzolvolimab holds significant potential to regulate MC differentiation and survival at a fundamental level, suggesting it may play a crucial role in the treatment of AD in the future.

Co‐citation analysis is a scientometric method used to explore the relationships between documents by analyzing the co‐occurrence of references, ⁴⁷ revealing the knowledge structure and academic networks within a research field. The clustering results identify 10 major clusters in the co‐citation network map, with the largest cluster being “Thymic Stromal Lymphopoietin” (#0), comprising 23 members. The primary cited work in this cluster is a systemic review published in 2004 in the Journal of Clinical Investigation, which puts emphasis on the advances in the pathophysiological mechanisms and treatment strategies for AD. Figure 7C provides a timeline view of these 10 key clusters, highlighting their temporal evolution and developmental trends. In general, the clustering timeline highlights the latest documents that are gradually gaining more citations, revealing emerging directions in the research field. As shown in Figure 7C, it presents a timeline perspective of these 10 key clusters, illustrating their temporal and evolutionary characteristics figure, cluster 5 (long‐term efficacy) and cluster 10 (gene expression) emerged earliest, while cluster 1 (new insight) and cluster 4 (signal introducer) represent the most recent research focuses, indicating shifts in research priorities over time. ⁴⁸

Additionally, burst detection, a data analysis algorithm developed by Kleinberg, ⁴⁹ was used in our co‐citation analysis to identify abrupt spikes in citation activity. Figure 7D illustrates that the earliest burst occurred in 2003, when Toyoda ⁵⁰ and colleagues proposed that neurogenic factors such as substance P and nerve growth factor (NGF) might regulate allergic responses in AD through interactions with immune inflammatory cells. They also suggested that elevated levels of these factors in AD patients are partly due to MC activation and proliferation. The most recent citation burst was observed in 2022. Notably, five studies experienced significant citation bursts and have maintained momentum to the present. Among these, a review by Langan SM, ⁵¹ published in the Lancet in 2020, has had a long‐lasting impact, with ongoing citation bursts. This review provides a comprehensive overview of AD epidemiology, pathogenesis and prevention and treatment strategies, and offers insights into future therapeutic approaches for AD.

Keywords visualization analysis provides a clearer understanding of the hot spots, frontiers and trends in the research field. It is commonly believed that as lexical pairs appear together more frequently within the same document, the relationship between these topics becomes stronger. Figure 8A illustrates the annual trends of the top 15 keywords, showing a remarkable increase in the frequency of terms such as TSLP and NF‐Kappa B, in addition to MCs and AD. Following this, we performed co‐occurrence analysis of keywords using VOSviewer, where highly central nodes often represent core concepts or key themes in the field. Keywords are color‐coded based on their appearance year: blue indicates earlier terms, while yellow denotes more recent ones. Initially, research focused on terms like histamine, anti‐histamine treatments, animal experiments and neurogenic factors such as NGF, reflecting early interests in AD, particularly exploring neuro‐immune interactions and the mechanisms of itching. By combining the findings from VOSviewer and CiteSpace, we were able to identify emerging research hotspots and frontiers: the role of oxidative stress in disease mechanisms, the imbalance of various T helper (Th) cell types in immune responses, skin barrier dysfunction, enhancing the quality of life for AD patients, sensory neurons and the development of biologics and small molecule drugs.

Finally, we utilized an online data analysis platform to compile a detailed list of the most extensively studied genes in this field. The results indicate that IL‐13, IL‐4, NFKB1, BCGF‐1 and CD4 have received significant research attention in MCs and AD. To investigate the potential molecular mechanisms of these genes, we used the STRING tool to generate a comprehensive gene interaction network. Simultaneously, we performed GO enrichment analysis on the related genes, which is displayed in a bubble chart. As shown in Figure 9C, the enrichment analysis reveals that these genes are primarily associated with the regulation of inflammatory response, positive regulation of leukocyte activation, positive regulation of cytokine production and positive regulation of cell activation. The gene interaction network elucidates the relationships and functional associations between genes, providing insights into the complex regulatory mechanisms of organisms and identifying new targets for disease diagnosis and treatment and supporting future targeted research and therapeutic interventions.

4.2. The role of MCs in AD

The pathogenesis of AD is intricate, characterized by the involvement of various immune cells and inflammatory cytokines. MCs are predominantly found in the skin and mucous membranes. As an immune cell with widespread distribution and diverse functions, they play a crucial role in mediating a variety of allergic diseases. MCs arise from pluripotent hematopoietic stem cells in the bone marrow, then circulate through the bloodstream and lymphatic system before differentiating and maturing in specific immune micro‐environments. Based on their phenotype and function, they can be classified into two categories: MMCs and CTMCs, and skin‐derived MCs had many characteristic features of CTMC. ⁷

MCs play a pivotal role in the pathogenesis of AD. Researchers have observed a significant increase in MC numbers within AD lesions. ⁵² This increase is attributed to the proliferation of skin‐resident mast cells (rMCs) and the targeted migration of bone marrow‐derived MC progenitors (BM‐derived MCps), which subsequently acquire a CTMC phenotype in the skin tissue. Additionally, repeated exposure to house dust mite antigen and staphylococcal enterotoxin B can induce an AD mouse model. However, Kit^−/− mice and Kit‐dependent MC‐deficient mice do not respond to these stimuli, making it difficult to induce AD symptoms in these models.

Nevertheless, the precise role of MCs in the pathogenesis of AD is still not fully understood. Upon activation, mast cells release numerous inflammatory mediators, including specific cytokines such as tumor necrosis factor (TNF) and interleukins, serine proteases like tryptase and chymase, ⁸ as well as histamine. Despite these known mediators, the endogenous regulators responsible for MC activation and the mechanisms underlying this process are yet to be fully understood. ¹¹ Research indicates that MCs contribute to the pathogenesis of AD primarily through the “IgE‐FcεRI‐histamine” pathway and the “MrgprB2/X2‐tryptase.” It is well understood that itching is a primary symptom of AD, yet the specific mediators causing itching in AD patients remain unidentified. ⁸ Extensive research indicates that IgE‐mediated MC activation, along with the release of MC‐derived inflammatory mediators, plays a significant role in the pathophysiology of itching. ⁵³ Upon IgE stimulation, MCs release both preformed and newly synthesized histamine, which then triggers itching. MC‐derived histamine is notably a powerful inducer of itching in AD, with histamine‐induced pruritus being a key diagnostic criterion for the condition. Collectively, these findings highlight the essential role of histamine not only as an indicator of MC degranulation but also as a significant factor in the development and exacerbation of itching associated with AD. Meanwhile, MCs secrete various type 2 inflammatory cytokines(IL‐4, IL‐13, IL‐31, etc.), exacerbating the immune imbalance in AD. ⁵⁴ In addition, some studies have shown that in AD, MCs are densely located in and around the epidermis, potentially stimulating neovascularization. These newly formed blood vessels facilitate the transport of complement components, inflammatory cells and antibodies to the epidermis, thereby enhancing defense against environmental antigens while sustaining chronic inflammation ⁵⁵ .

4.3. Current applications and prospects for the future

Effective prevention and treatment of atopic dermatitis necessitate a multifaceted approach. Therapies such as calcineurin inhibitors, topical corticosteroids and immunosuppressants are commonly employed to manage AD exacerbations. ⁵⁶ While these treatments can provide immediate symptom relief, their adverse effects make them unsuitable for long‐term use. Consequently, there is growing interest in finding and developing safe and effective drugs for AD treatment. Currently, no drugs specifically target MCs in AD. However, existing medications may indirectly reduce MC numbers or activation. Understanding the role of MCs in atopic dermatitis can lead to new therapeutic strategies. For instance, antihistamines ⁵⁷ can alleviate itching and reduce scratching behavior. Additionally, MC stabilizers like ketotifen and sodium cromoglycate can decrease MC‐mediated inflammation, thereby easing AD symptoms. ⁵⁸

A notable advancement is Barzolvolimab (CDX‐0159), a fully human anti‐KIT monoclonal antibody that blocks SCF‐induced KIT activation. ⁴⁶ A global, multicenter, randomized, double‐blind, parallel‐group, placebo‐controlled phase 3 study of this drug is currently in progress. Previous clinical trials have shown that Barzolvolimab is well‐tolerated, significantly depletes skin MCs rapidly and persistently, without affecting MC progenitor numbers or function. It also reduces circulating tryptase and significantly improves patients' quality of life. Researchers believe Barzolvolimab holds great potential for regulating MC differentiation and survival, making it a promising treatment for refractory type 2 inflammatory diseases such as AD. ⁵⁹ Conversely, no antagonists have been developed for clinical application targeting the Mrgpr family, another MC signaling pathway. Targeting MrgprX2 antagonists represents a promising molecular approach for future AD drug development. At present, numerous biologics and small molecule drugs targeting MCs are in various stages of development. Moreover, plant‐derived drugs are gaining attention. Studies have shown that Polyozellus multiplex, ⁴ an edible mushroom, can inhibit MC infiltration, degranulation and scratching behavior.

In addition to the traditional CTMC and MMC classifications, recent research has introduced more complex MC typologies. Based on surface markers (e.g., CD117, CD25, CD203c) and secreted cytokines (e.g., IL‐4, IL‐6, TNF‐α), MCs can be further subdivided. ⁶⁰ This detailed classification is important in research and clinical contexts, as different MC types play distinct roles in allergic reactions, inflammation and immune regulation. Understanding these subtypes can aid in developing targeted therapies for specific MC populations.

4.4. Weaknesses and strengths

We recognize that there are specific inherent constraints in our study. One significant limitation of bibliometric research is its dependence on citation‐based metrics, which can introduce biases, particularly citation bias. ⁶¹ , ⁶² Notably, we only searched the Web of Science Core Collection, excluding other databases such as PubMed and Scopus. Consequently, the identified articles may not fully represent the MCs and AD research landscape. Nevertheless, we believe that the selected publications sufficiently reflect the overall field, as WoSCC remains the most comprehensive and authoritative citation database for bibliometric research. ²⁹ Additionally, our literature search started in 2001, and the citation count of an article is correlated significantly with the year of publication, possibly overlooking recently published high‐quality papers with fewer citations. Finally, some metrics in this study may lack clarity. For example, organizations or journals may have used different names over time. Despite these limitations, this study represents the first bibliometric analysis of the relationship between MCs and AD, offering clinicians and researchers a comprehensive overview of research trends and historical developments, distinct from traditional narrative reviews. Furthermore, this study has the potential to highlight unexplored areas for future clinical trials to address relevant issues in this field. It can also help identify key authors and prominent journals, aiding novice researchers in selecting mentors and institutions and aligning their research goals with the priorities of stakeholders, decision‐makers and funding organizations in the clinical and scientific communities.

5. CONCLUSION

The potential underlying mechanisms of MCs in AD have been widely investigated in recent years. Nevertheless, several issues remain to be further addressed. Bibliometric analysis, through meticulous examination of previous researchers' academic articles, has significantly enhanced the elucidation of the impact of MCs on the development of AD. Using CiteSpace and Vosviewer, the main countries/regions, institutions, authors, journals, co‐cited references and keywords in this research field were identified. Based on the analysis, we can summarize that future research frontiers and hotspots in this field: the role of oxidative stress in pathogenesis; the imbalance of different types of T‐helper (Th) cells in immune responses; skin barrier and barrier dysfunction; improvement in quality of life; sensory neurons; biologics and small molecule drugs. Further research into the role of MCs in the development of AD is expected to yield new targeted therapeutic strategies. Therefore, there is legitimate hope that new prevention strategies and therapies specifically targeting the AD disease process will effectively reduce the global healthcare costs and morbidity burden. As advancements in data science and analytical methodologies continue to progress, the scope and depth of bibliometric applications are anticipated to expand significantly, driving progress within the field of dermatology, ultimately contributing to its advancement and transformation.

CONFLICT OF INTEREST STATEMENT

The authors declare that the research is conducted in the absence of any commercial or financial relationships. The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s).

ETHICS STATEMENT

This study does not involve human participants or animals and therefore did not require ethical approval.

Zuo W, Yue Z, Xu S, et al. Emerging trends and research hotspots in the relationship between mast cells and atopic dermatitis based on the literature from 2001 to 2024: A bibliometric and visualized analysis. Skin Res Technol. 2024;30:e70053. 10.1111/srt.70053

DATA AVAILABILITY STATEMENT

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.