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Journal of Inflammation Research logoLink to Journal of Inflammation Research
. 2026 Oct 1;19:621758. doi: 10.2147/JIR.S621758

Soluble Epoxide Hydrolase in Inflammatory and Immune Diseases: A Bibliometric and Visualization Analysis in 2000–2025

Tian Han 1,2,*, Zhen Yang 1,2,*, Weiye Zhang 1, Wen Hou 1,✉, Zhongyang Shen 1,2,✉
PMCID: PMC13637738  PMID: 42835807

Abstract

Background

Soluble epoxide hydrolase (sEH) is extensively involved in the pathophysiological processes of inflammatory and immune diseases. This study aims to systematically analyze the current research status, cooperation networks, and evolutionary trends in this field using bibliometric methods to provide a reference for future basic research and clinical translation.

Methods

Articles and reviews related to sEH, inflammation, and immunity published from January 1, 2000, to December 31, 2025, were retrieved from the Web of Science (WoS) and Scopus databases. VOSviewer, CiteSpace, and the bibliometrix package in R were utilized to perform visualization analysis of publication volume, distribution of countries and institutions, core authors, highly cited publications, and keywords.

Results

A total of 2240 publications were included in this study. The annual publication volume exhibited a steady upward trend, reaching a periodic peak in 2021. The United States ranked first globally in publication volume (908 publications). The University of California was the most contributing institution, and its scholar, Bruce Hammock, held a core position in both publication volume and academic impact. PNAS was the most cited journal in this field. Current research frontiers focus on pharmacodynamics, molecular docking, protein mechanisms, lipid chromatography mass spectrometry, and clinical translation studies.

Conclusion

This study presents the first systematic knowledge map of sEH in inflammatory and immune diseases. sEH inhibitors have emerged as highly promising targets for anti-inflammatory and immunomodulatory therapy. Clinical translation will be the key development direction for this field in the future.

Keywords: inflammation, immunity, soluble epoxide hydrolase, epoxyeicosatrienoic acid, epoxy fatty acid, bibliometric

Introduction

Lipid signaling molecules serve as central mediators in inflammation and immune regulation networks,1 playing critical roles in modulating oxidative stress in parenchymal cells and the activation of immune cells.2,3 Within the polyunsaturated fatty acid metabolic cascade, epoxy fatty acids (EpFAs) are biosynthesized via the cytochrome P450 (CYP) enzyme system.4 In vivo, these EpFAs are rapidly hydrolyzed by sEH to their corresponding dihydroxy fatty acids.5 Among the various epoxy fatty acids, arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs) are by far the most functionally significant, owing to their well-established roles as critical mediators of anti-inflammatory,6 vasodilatory,7 and cytoprotective responses.8 Consequently, sEH has emerged as a key metabolic node regulating systemic EETs levels. Utilizing sEH inhibitors to maintain EETs concentrations has become a vital strategy for treating inflammation-related diseases.9,10

Early research on sEH focused primarily on the cardiovascular system, such as blood pressure regulation and the amelioration of myocardial ischemia-reperfusion injury.11,12 With the progression of basic research, the physiological functions of sEH have been demonstrated to extend across broad metabolic and immune domains, including non-alcoholic fatty liver disease,13 acute inflammation induced by viral infections,14 and various chronic autoimmune diseases.15 The role of sEH inhibitors in alleviating endoplasmic reticulum stress,8 inhibiting the NF-κB signaling pathway,16 and regulating macrophage polarization17 underscores their substantial clinical potential in remodeling the inflammatory microenvironment. sEH inhibitors have been advanced into multiple ongoing clinical trials, including EC-5026,18,19 GSK2256294,20 and AR9281.21 All these candidates have demonstrated favorable safety profiles. Clinical translation represents an emerging research direction in this field.

Despite the continuous growth in research output regarding sEH in inflammatory and immune diseases, a systematic consolidation of the knowledge structure remains absent. Although narrative reviews have provided valuable summaries of the research basis and future perspectives in this area, their subjective nature limits the ability to detect the underlying cooperation patterns, evolutionary pathways, and emerging frontiers.22,23 Such critical information can only be effectively extracted through bibliometric approaches. Bibliometric and visualization analysis, as an effective tool for the quantitative evaluation of academic trends, utilizes mathematical methods to identify core countries, institutions, authors, and journals, along with collaboration networks, research hotspots, and evolutionary trajectories within specific domains.24 While bibliometric studies exist for other pharmacological fields,25–27 no specialized report has yet addressed the application of sEH in inflammatory and immune diseases.

This study retrieves literature from the WoS and Scopus databases and integrates multi-dimensional analysis tools, including VOSviewer, CiteSpace, and R-bibliometrix, to perform a statistical analysis of publications from 2000 to 2025. The objective is to accurately identify core research groups, evolutionary frontiers, and future trends, providing data support and theoretical references for the development of novel sEH-targeted drugs and clinical translation research.

Methods

Data Sources and Search Strategy

The Web of Science (WoS) Core Collection and Scopus databases were searched for literature published between January 1, 2000, and December 31, 2025. The search string was defined as follows: TS=(“soluble epoxide hydrolase” OR “epoxide hydrolase 2” OR “EPHX2” OR “epoxyeicosatrienoic acid” OR “dihydroxyeicosatrienoic acid” OR “epoxy fatty acid” OR “dihydroxy fatty acid”) AND TS=(“inflammation” OR “inflammatory” OR “immune” OR “immunity” OR “immune response” OR “immune regulation” OR “immune tolerance” OR “autoimmune” OR “autoimmunity” OR “chronic inflammatory disease” OR “innate immunity” OR “adaptive immunity” OR “macrophage” OR “monocyte” OR “T cell” OR “B cell” OR “cytokine” OR “chemokine” OR “oxidative stress” OR “endothelial dysfunction” OR “vascular inflammation” OR “chronic inflammation” OR “acute inflammation” OR “rheumatoid arthritis” OR “systemic lupus erythematosus” OR “psoriasis” OR “multiple sclerosis” OR “asthma” OR “allergic inflammation” OR “inflammatory bowel disease” OR “ulcerative colitis” OR “Crohn disease” OR “sepsis” OR “acute respiratory distress syndrome” OR “atherosclerosis” OR “cardiovascular inflammation” OR “hypertension” OR “diabetes” OR “diabetic inflammation” OR “obesity-induced inflammation” OR “nonalcoholic steatohepatitis” OR “kidney inflammation” OR “renal injury” OR “liver inflammation” OR “neuroinflammation”) NOT TS=(“microsomal epoxide hydrolase” OR “EPHX1”).

A systematic literature search was performed in the WoS and Scopus databases using predefined search strategies, yielding 2,001 and 2,055 publications, respectively. The search was restricted to articles and reviews published in English between January 1, 2000, and December 31, 2025. After applying these eligibility criteria, 1,778 publications from WoS and 1,759 publications from Scopus were retained for further analysis. The detailed search syntaxes, parameters, and operational logs are provided in Supplementary Table S1. Deduplication of the records exported from the WoS and Scopus databases was performed using Python software. The deduplication process was based on the bibliographic metadata of the 1,778 WoS publications, which served as the reference standard for matching. As a result, 1,297 duplicate records were identified and removed, yielding a final set of 2,240 unique publications for subsequent analysis. All search procedures, deduplication, and data verification were independently conducted by two authors (Tian Han and Zhen Yang) to ensure accuracy. Consensus was achieved between the two reviewers prior to proceeding with the bibliometric analysis. All relevant metadata were exported in.txt format and are provided in the Supplementary Material for subsequent analyses. The detailed screening and deduplication process is shown in Figure 1.

Figure 1.

Flowchart of literature screening and analysis for epoxide hydrolase studies. A flowchart detailing the literature screening and analysis process for studies on soluble epoxide hydrolase in inflammatory and immune diseases. The process begins with a search formula targeting specific terms related to inflammation and immune response. A total of 2001 documents were retrieved from the Web of Science and 2055 from Scopus. Publications were excluded based on date, document type and language, resulting in 1778 and 1759 relevant publications from Web of Science and Scopus, respectively. Deduplication using Python identified 1297 duplicate records, leading to 2240 unique publications. The analysis focuses on publications, countries, institutions, authors, journals, documents and keywords. Tools used include VOSviewer 1.6.20, CiteSpace 6.4. R1 and R-bibliometrix 4.3.3. The study is titled ′Soluble Epoxide Hydrolase in Inflammatory and Immune Diseases: A Bibliometric and Visualization Analysis in 2000-2025.′.

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Methodological flowchart of the literature screening and bibliometric analysis.

Bibliometric and Visual Analysis Methods

Three bibliometric tools were combined to analyze the research landscape from multiple perspectives. VOSviewer (version 1.6.20) was used to construct and visualize co-citation, bibliographic coupling, and collaboration networks. It was also employed to generate the geospatial distribution of global output and identify academic associations among research groups. CiteSpace (version 6.4.R1) served to identify research frontiers and core publications by generating journal dual-map overlays, keyword co-occurrence clusters, and citation bursts. Additionally, the Bibliometrix package in R (version 4.3.3) provided comprehensive statistical analysis and assessed the academic impact of authors, journals, and institutions using indicators such as the H-index. Supplementary Table S2 presents the detailed parameters of the three bibliometric tools. This integrated approach allowed for a systematic interpretation of the current status and evolutionary trends of sEH in inflammatory and immune diseases.

Results

Analysis of Publication Volume Trends

Between 2000 and 2025, a total of 2,240 publications regarding sEH in inflammatory and immune diseases were published. As illustrated in Figure 2A, the annual publication volume followed an overall upward trend, which can be divided into two distinct stages: an initial growth phase from 2000 to 2012, where annual output rose steadily from single digits to fewer than 100 publications; and a rapid development phase from 2013 onward, where annual output consistently exceeded 100 publications. This trajectory indicates that research intensity in this field has increased significantly and remained stable at a high level. Statistical analysis reveals that publication volume peaked in both 2021 and 2025. The surge in 2021 may be closely related to global research on the “cytokine storm” associated with COVID-19, further corroborating the academic value of sEH as an anti-inflammatory target for managing acute inflammatory stress.14

Figure 2.

A composite with a line graph, a stacked bar chart, a world collaboration map and a network graph. Image A shows a line graph with a dotted trend line. The x-axis covers 2000 to 2025 and the y-axis ranges from 0 to 300 publications annually. The solid line rises from 10 in 2000 to 150 in 2025, with some fluctuations, while the dotted trend line forecasts 250 by 2025. The equation y = 10.555e superscript 0.0115x and R superscript 2 = 0.7494 are included. Image B presents a horizontal stacked bar chart with ′N. of Documents′ on the x-axis (0 to 600) and ′Countries′ on the y-axis. The USA leads with over 600 documents, followed by China (400), Germany (120) and the UK (90). Other countries have fewer than 60 documents. The legend shows collaboration types SCP and MCP. Image C depicts a world map with nodes and lines for collaborations. Key nodes are USA, Canada, Germany, Sweden, Russia, China, Japan and Australia, with smaller nodes worldwide. Image D displays an institutional collaboration network with nodes like Univ California, Goethe Univ, Univ Wisconsin, Stanford Univ and others linked together.

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Publication volume, country and institution distribution, and collaboration landscape in this field. (A) Global trends in publication output and academic impact (2000–2025). (B) Publication volume by the corresponding author’s country, categorized into Single-Country Publications (SCP, blue) and Multiple-Country Publications (MCP, red). (C) Geospatial distribution and network visualization of international research collaborations generated via VOSviewer, illustrating the connectivity among major contributing countries/regions. (D) Institutional collaboration network visualization generated via VOSviewer.

Distribution of Major Countries and Collaboration Networks

As shown in Table 1, the United States published the highest number of publications in this field, with a total of 908 publications accounting for 40.53% of the global output. This was followed by China (463 publications, 20.67%), Germany (194 publications, 8.66%), Japan (98 publications, 4.38%), Canada (82 publications, 3.66%), and the United Kingdom (65 publications, 2.90%). Regarding academic impact, although China ranks second globally in publication volume, its average citations (34.52) remains lower than those of the United States (53.21), Germany (57.02), Japan (40.15), Canada (49.95), and the United Kingdom (53.57). This indicates that while China maintains a large research scale, a disparity in core influence persists compared to developed nations.

Table 1.

Top 10 Countries/Regions for Research Related to Soluble Epoxide Hydrolase in Inflammatory and Immune Diseases

Rank Country Publication Counts Percentage % Total Citations Average Citations
1 USA 908 40.53 48,316 53.21
2 China 463 20.67 15,982 34.52
3 Germany 194 8.66 11,062 57.02
4 Japan 98 4.38 3935 40.15
5 Canada 82 3.66 4096 49.95
6 United Kingdom 65 2.90 3482 53.57
7 Italy 61 2.72 2199 36.05
8 South Korea 56 2.50 1845 32.95
9 Czech Republic 55 2.46 1605 29.18
10 Poland 40 1.79 784 19.6
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The substantial disparity in average citations between China and developed nations is more appropriately understood as the result of a combination of structural factors, including the more recent age profile of Chinese publications, the relatively peripheral position of Chinese scholars in the global citation network, and language-related barriers to dissemination. From the perspective of scientific collaboration, the analysis of corresponding authors’ countries in Figure 2B demonstrates that Multiple-Country Publications (MCP) constitute a significant proportion of the output from core countries. The global collaboration network (Figure 2C) further illustrates the formation of a dense collaborative framework with North America (USA, Canada), Europe (Germany, UK), and East Asia (China, Japan) serving as primary nodes. This landscape underscores the necessity of international cooperation in driving progress within this research domain.

Core Research Institutions and Their Collaboration Networks

At the institutional level, the University of California demonstrates a dominant position in this field, with 450 publications published. This volume accounts for 20.09% of the global total and nearly half (49.56%) of the total output from the United States. Its publication scale significantly exceeds that of the second-ranked institution, the Medical College of Wisconsin (94 publications). As shown in Table 2, among the top six institutions by publication volume, four are located in the United States, further confirming the academic leadership of the United States in this domain. The institutional collaboration network visualization (Figure 2D) reveals that the University of California possesses extremely high centrality, serving as the core hub for global academic exchange and scientific collaboration in this field.

Table 2.

Top 10 Institutions for Research Related to Soluble Epoxide Hydrolase in Inflammatory and Immune Diseases

Rank Institution Publications Counts Country Total Citations
1 University of California 450 USA 25416
2 Medical College of Wisconsin 94 USA 5120
3 National Institute of Environmental Health Sciences 72 USA 4652
4 Goethe University 70 Germany 5072
5 Huazhong University of Science and Technology 62 China 3734
6 University of Texas Southwestern Medical Center 62 USA 2820
7 Charité – Universitätsmedizin Berlin 60 Germany 1812
8 New York Medical College 60 USA 1973
9 Harvard University 45 USA 3256
10 Institute for Clinical and Experimental Medicine, Prague, Czechia 43 Czechia 877
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Core Authors and Their Collaboration Networks

The distribution of core authors in this field exhibits a high degree of academic concentration. As shown in Table 3, Bruce Hammock is the most prolific scholar in this domain, with 398 publications. His output represents 17.77% of the global total and 43.83% of the total volume from the United States, reflecting his significant influence in the promotion and application of sEH-related studies. Other leading core authors include Christophe Morisseau (184 publications), Sung-Hee Hwang (101 publications), and John Imig (96 publications). Notably, the top seven authors by publication volume are all affiliated with United States research institutions. The top three are affiliated with the University of California. This distribution further confirms the academic dominance of the United States and the University of California in this field.

Table 3.

Top 10 Authors for Research Related to Soluble Epoxide Hydrolase in Inflammatory and Immune Diseases

Rank Author Publication Counts Total Link Strength Country Total Citations Institution
1 Bruce Hammock 398 1111 USA 23518 University of California
2 Christophe Morisseau 184 557 USA 9804 University of California
3 Sung-Hee Hwang 101 428 USA 4607 University of California
4 John Imig 96 323 USA 6056 Medical College of Wisconsin
5 Darryl Zeldin 88 287 USA 5561 National Institute of Environmental Health Sciences
6 John Falck 86 242 USA 3682 University of Texas Southwestern Medical Center
7 Jun Yang 82 305 USA 3867 University of California
8 Ludek Cervenka 45 260 Czechia 916 Institute for Clinical and Experimental Medicine, Prague, Czechia
9 Ingrid Fleming 39 49 Germany 3534 Goethe University
10 Daowen Wang 39 97 China 3492 Huazhong University of Science and Technology
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Analysis of scientific collaboration (Figure 3A) reveals the network among core authors. Bruce Hammock serves as the primary node of academic cooperation, with a total link strength of 1,111, far exceeding that of other scholars. This high centrality reflects his extensive research partnerships with multiple global teams. Chronologically, Figure 3B illustrates the evolution of research output for the top 10 authors. Bruce Hammock and Christophe Morisseau have maintained high and stable academic productivity from 2000 to 2025. This consistency reflects the continuity and depth of their research efforts in this field, highlighting that the long-term commitment of core scholars is a central driver of breakthroughs in this area.

Figure 3.

A network visualization and timeline of author collaborations and productivity. The image A shows a network visualization of author collaborations using VOSviewer. Bruce Hammock is the central node, indicating extensive research partnerships. Other authors like Hwang Sung Hee and Imig John D. are also connected, showing a web of academic cooperation. The image B shows a timeline of the top 10 authors′ production from 2000 to 2025. Authors like Hammock B. D. and Morisseau C. have maintained consistent productivity. The x-axis represents the year and the y-axis lists authors. The size of the circles indicates the number of articles, while the color intensity represents total citations per year.

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Author collaboration and timeline production in this field. (A) Author collaboration network visualization generated via VOSviewer. (B) Top 10 authors’ production over time.

Distribution of Core Journals and Citation Analysis

Statistical analysis of publication sources identifies the core platforms for academic exchange and the paths of knowledge dissemination within this field. As shown in Table 4 and Figure 4A, Prostaglandins and Other Lipid Mediators is the most prolific journal (100 publications), with an H-index of 30, reflecting its specialized foundation in lipid metabolism research. However, regarding academic influence, PNAS holds a preeminent position. Although it has a relatively low publication volume (37 publications), it recorded the highest total citation frequency (3,828) and H-index (35), underscoring the leading role of high-quality basic research in this domain. Furthermore, the high citation counts of the Journal of Medicinal Chemistry (3,128) and Hypertension (2,639) reflect the significant focus on sEH research in medicinal chemistry development and cardiovascular applications.

Table 4.

Top 10 Journals for Research Related to Soluble Epoxide Hydrolase in Inflammatory and Immune Diseases

Rank Journal Publication Counts IF (2026) Total Citations Journals’ Local Impact by H Index
1 PNAS 37 9.5 3828 35
2 Prostaglandins and Other Lipid Mediators 100 2.6 3517 30
3 Hypertension 37 9.8 2639 27
4 Plos One 40 2.8 1484 24
5 Journal of Medicinal Chemistry 38 7.3 3128 23
6 Frontiers in Pharmacology 46 5.4 1285 22
7 Journal of Lipid Research 26 4.9 2306 21
8 Bioorganic and Medicinal Chemistry Letters 27 2.3 810 20
9 International Journal of Molecular Sciences 63 5.6 2233 20
10 American Journal of Physiology-Heart and Circulatory Physiology 27 3.9 1115 18
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Figure 4.

Four plots of journal sources, journal networks, co citation clusters and author keyword trends over time. The image A showing a line chart of articles by source rank with a shaded region labeled, Core Sources. The x axis lists journal names as categories. The y axis is labeled, Articles, with ticks at 0, 20, 40, 60 and 80. The line starts near 80 at the leftmost journal, drops to about 65, then to about 45, then to about 35, then to about 30, then to about 20 and continues declining in small steps to near 0 at the far right. The image B showing a VOSviewer network graph of journals as labeled nodes connected by many curved links. Large central labels include, Prostaglandins and Other Lipid Mediators, PNAS, Journal of Medicinal Chemistry, Hypertension and Frontiers in Pharmacology, with many smaller journal labels surrounding. The image C showing a second VOSviewer network graph with denser clustering and many labeled journal nodes and links. Prominent labels include, PNAS, Hypertension, Journal of Medicinal Chemistry, Prostaglandins and Other Lipid Mediators and several American Journal of Physiology titles. The image D showing a Sankey style alluvial diagram linking three columns labeled, AU, DE and SO. The AU column lists multiple author names as stacked blocks. The DE column lists terms including, soluble epoxide hydrolase, epoxyeicosatrienoic acid, arachidonic acid, inflammation and hypertension. The SO column lists journal titles including, Prostaglandins and Other Lipid Mediators, International Journal of Molecular Sciences, Frontiers in Pharmacology, Hypertension and PNAS. Curved bands connect authors to terms and terms to journals.

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Journal distribution and citation analysis in this field. (A) Distribution of core sources based on Bradford’s Law, identifying the key academic vehicles within this field. (B) Visualization of the journal network generated via VOSviewer, illustrating academic associations and interactions among journals. (C) Journal co-citation network generated via VOSviewer, identifying key academic hubs and core exchange platforms for research within this field. (D) Trend chart illustrating the evolution of authors (AU), author keywords (DE), and source Journals (SO).

Visualized journal co-citation networks (Figure 4B and C) further identify core nodes. PNAS, Journal of Biological Chemistry, Prostaglandins and Other Lipid Mediators, and Hypertension collectively form the central cluster of the network, serving as the primary knowledge sources in this field. As illustrated in Figure 4D, the trend chart shows the evolution of authors (AU), author keywords (DE), and source Journals (SO). These primary source journals are closely associated with leading authors, including Bruce Hammock, through core keywords such as sEH, EETs, hypertension, and inflammation.

Analysis of Highly Cited Publications and Research Hotspot Evolution

Highly cited publications serve as the cornerstone of the knowledge map within a specific research field. As shown in Table 5, the study published by Wang B et al28 in the Signal Transduction and Targeted Therapy in 2021 possesses the highest academic influence in this field, with 1,720 total citations. This research systematically elucidated the arachidonic acid metabolic network, revealing that cyclooxygenase, lipoxygenase, and CYP pathways generate bioactive lipids, with particular emphasis EETs and sEH, which serve as critical molecular switches that confer cardiovascular protection and tumor metastasis.

Table 5.

Top 10 Most Cited Publications for Research Related to Soluble Epoxide Hydrolase in Inflammatory and Immune Diseases

Rank Title The First Author Journal Total Citations Publication Year
1 Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets Wang B Signal Transduction and Targeted Therapy 1720 2021
2 P-450 metabolites of arachidonic acid in the control of cardiovascular function Roman RJ Physiological Reviews 1264 2002
3 Facing up to the global challenges of ageing Partridge L Nature 1212 2018
4 The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules Talele TT Journal of Medicinal Chemistry 884 2016
5 Endothelial dysfunction and vascular disease - a 30th anniversary update Vanhoutte PM Acta Physiologica 749 2017
6 Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases Imig JD Nature Reviews Drug Discovery 578 2009
7 Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function Spector AA Progress in Lipid Research 554 2004
8 Role of peroxisomes in ROS/RNS-metabolism: implications for human disease Fransen M Biochimica et Biophysica Acta-Molecular Basis of Disease 552 2012
9 Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health Morisseau C Annual Review of Pharmacology and Toxicology 493 2013
10 Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology Buczynski MW Journal of Lipid Research 446 2009
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Other pivotal studies include the foundational work by Morisseau C et al23 (2013), which explicitly identified sEH as a therapeutic target for human health, and the study by Talele TT et al29 (2016), which identified the critical role of the cyclopropyl fragment in optimizing the pharmacological properties of preclinical drug molecules and sEH inhibitors. As illustrated in Figure 5A, the top 10 most cited publications collectively constitute a robust knowledge base, with research scopes ranging from sEH enzymatic characterization to therapeutic targets for diseases.

Figure 5.

Two bibliometric plots of global citation counts and citation burst timelines for references. Image A is a horizontal lollipop bubble chart ranking documents by global citations. The y-axis lists 10 references, including Wang B (2021) with 1720 citations and Buczynski M W (2009) with 391 citations. The x-axis shows citation counts with markers at 0, 500, 1000 and 1500. Each document′s citation count is marked, with Wang B (2021) having the highest at 1720 and Buczynski M W (2009) the lowest at 391. Image B is a citation burst timeline chart from 2000 to 2025, with references listed alongside DOI, Year, Strength, Begin and End columns. The timeline shows burst intervals from the early 2000s to 2025, with years like 2002, 2004, 2005, 2007, 2009, 2010, 2011, 2012, 2013, 2015, 2016, 2017, 2018, 2020 and 2021 appearing in the Year column. Multiple rows extend into 2025, indicating ongoing citation bursts.

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Highly cited publications and citation burst analysis in this field. (A) Top 10 most cited publications. (B) Top 25 references with the strongest citation bursts identified via CiteSpace, illustrating the temporal evolution of research hotspots.

Citation burst analysis of references (Figure 5B) reveals that research hotspots in this field exhibit significant stage-wise evolutionary characteristics over time. Early research (2004–2009) primarily focused on the enzymatic properties of sEH and explored its potential as a novel drug target. Subsequently, between 2005 and 2014, the academic focus shifted toward validating the biological effects of sEH in cardiovascular disease and acute inflammation models. From 2012 onward, application research on sEH inhibitors gradually expanded into multiple fields, such as liver disease, metabolic disorders, and the neuroinflammatory system, demonstrating broad therapeutic potential. Recent research frontiers (2017–2023) have further deepened, with focus shifting toward investigating the underlying molecular mechanisms and precise targets of sEH in inflammatory microenvironment remodeling and complex immune regulation. This transition indicates that this field has progressed from phenotypic observation to a stage of molecularly precise intervention.

Keyword Co-Occurrence and Research Hotspot Analysis

Keyword co-occurrence analysis is a fundamental method for revealing the core framework and thematic structure of research within a specific field. As illustrated in Figure 6A, “soluble epoxide hydrolase,” “epoxyeicosatrienoic acids,” “inflammation,” “hypertension,” and “metabolism” are the most frequently occurring terms, constituting the core research thread. Based on the clustering analysis of high-frequency keywords (Figure 6B), 11 primary research hotspots were identified and categorized into four dimensions: molecular targets (eg, sEH, EETs, and CYP2C19), associated diseases (eg, hypertension and high-fat diet-induced pathological states), molecular mechanisms (eg, nitric oxide and transcription factor RelA signaling pathways), and research techniques (eg, drug development and mass spectrometry).

Figure 6.

Four-part infographic on keyword analysis in research, showing word cloud, clusters, timeline and citation bursts. A word cloud highlights ′soluble epoxide hydrolase′, ′epoxyeicosatrienoic acids′, ′inflammation′ and ′hypertension′ as prominent terms. A cluster map visualizes research domains like ′nitric oxide′, ′mass spectrometry′ and ′drug discovery′. A timeline view illustrates the progression of keyword clusters, including ′hypertension′, ′soluble epoxide hydrolase′ and ′epoxyeicosatrienoic acids′. A table lists the top 25 keywords with citation bursts, such as ′arachidonic acid′, ′cytochrome p450′ and ′blood pressure regulation′, showing their strength and duration from 2000 to 2025.

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Thematic clustering and temporal evolution of keywords in this field. (A) Keyword mapping quantity map. (B) Keyword clusters visualization highlighting the primary research domains. (C) Timeline view of keyword clusters illustrating the chronological progression and shifting research focus. (D) Top 25 keywords with the strongest citation bursts, identifying the dynamic evolution of research hotspots and emerging frontiers within this field.

The keyword timeline view (Figure 6C) indicates that these hotspots received extensive attention during the early stages of research, with academic collaboration across different themes intensifying over time. The citation burst analysis of high-frequency keywords (Figure 6D) reveals that the five terms with burst windows between 2020 and 2025, namely pharmacodynamics, protein, mechanisms, molecular docking, and lipid chromatography mass spectrometry. These collectively represent the research frontiers of this field. Furthermore, with ongoing advances in protein mechanisms and pharmacodynamics, clinical translation emerges as a central and pivotal direction within the field.

Discussion

Soluble epoxide hydrolase (sEH) plays a critical role in inflammatory and immune diseases. Its primary mechanism involves regulating the accumulation of EETs within the AA metabolic pathway, which subsequently influences cellular physiology and signal transduction.30–32 These processes modulate inflammatory and immune functions across various organs and systems, including the cardiovascular, respiratory, hepatic, and nervous systems.22,23 This study utilized multi-dimensional bibliometric and visualization analysis of publication volume, countries, institutions, authors, journals, highly cited publications, and keywords to clarify the current research status and developmental trends of sEH in inflammatory and immune diseases.

Analysis of Publication Volume, Countries, Institutions, Authors, Journals, and Highly Cited Publications

A total of 2,240 relevant publications were retrieved for this study. From 2000 to 2025, the annual publication volume increased progressively, indicating sustained and stable research interest in this field. Global output is primarily concentrated in a few nations, with the United States, China, and Germany leading in total publications. Comparative data show that the United States ranks first in both publication volume (908 publications) and average citations (53.21). China ranks second in output scale (463 publications) and average citations (34.52). Institutional and author analyses identify the University of California and Bruce Hammock as the most productive institution and scholar, respectively.

As a pioneer in this field, Professor Hammock’s research encompasses enzyme activity assays, inhibitor development, and disease model validation. His central position in the author collaboration network underscores a research environment marked by highly concentrated academic resources and collaborative patterns,33,34 with contributions that vastly outpace those of any other researcher worldwide. In line with our findings, the recent decline in the number of publications in this field may be, in part, attributable to his passing. We wish to take this opportunity to express our deepest respect and tribute to Professor Hammock. Looking ahead, the departure of this prominent figure is likely to reshape the network of core authors and collaborative partnerships in this field. Nonetheless, we remain optimistic about the continued scientific progress and clinical translation of sEH-related research.

Regarding the dissemination and citation of academic achievements, Prostaglandins and Other Lipid Mediators (IF=2.6) is the most prolific journal due to its focus on lipid metabolism, while PNAS (IF=9.5) achieved the highest total citation rate through its publication of high-quality basic research. Analysis of the top 10 most cited publications reveals that this field is rooted in the deep exploration of sEH molecular targets. These core studies validated the function of the sEH/EET axis in diverse disease, including cardiovascular,11,12 hepatology, metabolic disorders,13 and neuroimmunology.35,36 As research into basic mechanisms deepens, the therapeutic potential of sEH inhibitors is increasingly emphasized in clinical translation studies.

Analysis of Keywords and Research Hotspots

Through in-depth analysis of keyword mapping and clustering, this study identified 11 core research hotspots, which were systematically explored across four dimensions: associated diseases, molecular targets, molecular mechanisms, and research techniques. The literature cited in this section for discussing the biological mechanisms of the sEH/EET axis was selected from the publications included in the bibliometric analysis. These studies primarily constitute the research background of this field and are closely related to its research hotspots and emerging frontiers.

Regarding associated diseases, sEH inhibitors exhibit broad clinical value in treating hypertension and systemic injuries induced by a high-fat diet. Studies confirm that sEH inhibitors improve vascular endothelial function, reduce blood pressure, and alleviate myocardial inflammation.30,31 For pathological states caused by high-fat diets, sEH inhibitors effectively mitigate hepatic steatosis, renal injury, and pancreatic β-cell damage, with mechanisms involving reduced lipogenesis, improved insulin resistance, and alleviated endoplasmic reticulum stress.37 In 2021, Luo J et al38 reported in the Journal of Biological Chemistry that the sEH inhibitor TPPU improves insulin resistance and hypertension in high-fat/high-salt diet-induced mice.

Regarding molecular targets, sEH serves as the key hydrolytic enzyme regulating EETs degradation; its biological value lies primarily in maintaining intracellular EETs levels through activity inhibition to exert tissue-protective effects.32 CYP2C19, a critical synthase producing EETs in AA metabolism, can similarly maintain elevated EETs levels upon overexpression.28 In 2011, Wagner K et al39 reported in Prostaglandins and Other Lipid Mediators that sEH participates in pain signaling regulation by modulating the anti-inflammatory and analgesic activities of EETs metabolites. In 2023, Cho HY et al40 reported in Pharmaceuticals that CYP2C19 is highly expressed in M2 macrophages and promotes their polarization by generating PPARγ agonists 11,12-EET and 14,15-EET.

At the molecular mechanism level, the regulation of nitric oxide and the transcription factor RelA signaling pathway by the sEH/EET axis has received widespread attention. By elevating EETs levels, sEH inhibitors can suppress the expression of inducible nitric oxide synthase, thereby reducing NO production to alleviate inflammatory responses.41 In immune signal transduction, EETs can block NF-κB pathway, subsequently inhibiting the transcription of pro-inflammatory cytokines and chemokines such as IL-6 and TNF-α.16 Additionally, sEH inhibitors regulate immune cell phenotypes by inhibiting pro-inflammatory macrophage polarization17 and increasing the proportion of Tregs,42 which accelerates inflammatory resolution and tissue repair.

Finally, in terms of research techniques, advancements in drug development and mass spectrometry have significantly driven this field. Drug development focuses on optimizing the pharmacodynamic and pharmacokinetic properties of sEH inhibitors, with several high-efficiency candidates currently entering clinical trials.18–21 The application of mass spectrometry has markedly enhanced the sensitivity for detecting EETs metabolites and sEH enzymatic activity. In 2022, Lu Y et al43 established a sensitive and reliable UPLC-MS/MS method in Analytical and Bioanalytical Chemistry for the quantitative detection of eicosanoids in human serum.

Analysis of Research Frontiers and Development Trends

By analyzing highly cited publications and the evolution of keywords, this study identifies five core frontier areas emerging between 2020 and 2025: pharmacodynamics, molecular docking, protein mechanisms, lipid chromatography mass spectrometry, and clinical translation. The literature cited in this section for discussing the biological mechanisms of the sEH/EET axis was selected from the publications included in the bibliometric analysis. These studies primarily constitute the research background of this field and are closely related to its research hotspots and emerging frontiers.

In pharmacodynamics research, the phenotypic effects of sEH inhibitors in inflammatory and immune diseases have been widely verified. Current research focus is shifting toward precise investigation of dosage and underlying mechanisms. Molecular docking technology is extensively utilized to predict the binding affinity between small molecule ligands and the sEH active site. Using molecular docking, Dang J et al44 first identified that zein peptides possess sEH inhibitory activity, and Phong NV et al45 reported the sEH inhibitory activity of cembranoid diterpenes 3 and 9.

Protein mechanism research remains a central direction, with emphasis on sEH enzymatic activity, protein conformational changes, and the resulting signaling cascades. In 2022, Zhang CY et al46 reported that PTUPB enhances autophagy and inhibits hepatocyte senescence via the Sirt1/PI3K/AKT/mTOR pathway, thereby improving high-fat diet-induced non-alcoholic fatty liver disease in mice. In 2023, Gao L et al47 found that the sEH inhibitor TPPU induces H-type angiogenesis by upregulating the SLIT3/ROBO1/YAP1/HIF-1α signaling pathway, promoting the coupling of angiogenesis and osteogenesis to accelerate bone regeneration and repair.

The high-throughput nature of lipid chromatography mass spectrometry provides technical support for the qualitative and quantitative analysis of eicosanoid metabolites and sEH enzymatic activity in complex samples. In 2024, Anita NZ et al48 used lipid chromatography-mass spectrometry to determine that elevated CYP450-sEH metabolite levels in patients with type 2 diabetes correlate with declined executive function. In 2023, Yu D et al49 reported that an increased ratio of linoleic acid-derived sEH metabolites is associated with imaging markers of small vessel disease, such as lacunar infarcts and white matter hyperintensities, as well as temporal lobe atrophy.

Finally, clinical translation has emerged as a frontier research topic in this field, aiming to convert basic mechanistic findings into clinical diagnostic and therapeutic tools. As the application of sEH inhibitors and EETs expands across inflammatory and immune diseases, multiple clinical trials are progressing. sEH inhibitors have been advanced into clinical trials, including EC-5026, GSK2256294, and AR9281. EC-5026, which was developed by EicOsis LLC, a company co-founded by Professor Bruce Hammock, is currently being evaluated in Phase 1/2 clinical trials for the treatment of Parkinson’s disease and chronic pain.18,19 GSK2256294, developed by GlaxoSmithKline, is under investigation in a Phase 1b trial for subarachnoid hemorrhage.20 AR9281, developed by Arete Therapeutics, was previously investigated in clinical trials for hypertension and diabetes.21 The clinical trials of sEH inhibitors demonstrated a favorable safety profile, with no adverse events attributable to the study drugs, highlighting their substantial potential for clinical translation. Future research will continue to focus on the deep resolution of target mechanisms and the translation of these discoveries into viable therapeutic strategies to improve human health and longevity.

Strengths and Limitations

This study possesses several notable strengths. First, it represents the systematic bibliometric and visualization analysis specifically focusing on the role of sEH in inflammatory and immune diseases. The convergent application of VOSviewer, CiteSpace, and R-bibliometrix affords a multi-dimensional interpretation of the field’s intellectual structure and evolutionary dynamics. Furthermore, the retrieval strategy utilized both the WoS and Scopus databases, ensuring a comprehensive collection of high-quality publications spanning a 25-year period.

Despite these contributions, several limitations should be acknowledged. Due to the inherent methodological limitations of bibliometric analysis, we were unable to assess the quality of the included studies. There may be a publication bias toward positive results among the publications incorporated in our analysis. In addition, recently published literature may have been underrepresented owing to lower citation counts and consequently reduced scholarly impact within the bibliometric assessment. Furthermore, our keyword-based search strategy may have inadvertently overlooked relevant studies that employed alternative or synonymous terminology. Additionally, while bibliometric analysis effectively maps research trends and hotspots through mathematical methods, it relies on metadata and citation metrics rather than providing direct experimental validation of biological mechanisms.

Conclusion

This study represents the first systematic bibliometric and visualization analysis of the research landscape concerning sEH in inflammatory and immune diseases. By evaluating 2,240 publications from 2000 to 2025, we have demonstrated that annual research output has entered a phase of rapid development, with the United States and the University of California emerging as the dominant contributors to global knowledge. Professor Bruce Hammock holds a central position in the academic collaborative network, reflecting a field characterized by highly concentrated academic resources. Thematic evolution analysis reveals that research focus has transitioned from early enzymatic characterization and cardiovascular functional validation toward the current frontiers of advanced pharmacodynamic evaluation. With growing insights into the molecular mechanisms of the sEH/EET axis, sEH inhibitors have become widely recognized as highly promising candidates for anti-inflammatory and immunomodulatory therapy. Consequently, clinical translation represents the core trajectory of this field, and transforming mechanistic insights into actionable therapeutic strategies will remain the research priority.

Acknowledgments

We would like to express our profound gratitude and respect to the late Professor Bruce Hammock, whose pioneering contributions to the sEH field have laid the foundation for this work. His legacy will continue to inspire and guide future research in this area.

Funding Statement

No funding was received.

Data Sharing Statement

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

Author Contributions

Tian Han: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Validation; Writing - original draft. Zhen Yang: Formal analysis; Methodology; Software; Visualization; Writing - original draft. Weiye Zhang: Formal analysis; Resources; Writing - review and editing. Wen Hou: Investigation; Project administration; Writing - review and editing. Zhongyang Shen: Conceptualization; Supervision; Writing - review and editing.

All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

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

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