Research hotspots and trends on bee venom therapy: A bibliometric and visualization analysis from 2004 to 2024

Abstract

Background and purpose:

Bee venom therapy (BVT) is widely used to treat various diseases. This study aimed to analyze the current status, research hotspots, and trends to guide future investigations.

Methods:

Literature related to BVT from 2004 to 2024 was retrieved from the Web of Science core collection database. By using CiteSpace 6.2.R7 and VOSviewer 1.6.20, bibliometric and visual analyses were carried out for different categories, such as countries/regions, institutions, authors, references, and keywords.

Results:

A total of 493 studies were included. This field is mainly led by Asian countries, South Korea, Kyung Hee University, and Roh Dae-Hyun, who were the most prolific country, institution, and author, respectively. “Therapeutic application of anti-arthritis, pain-releasing, and anticancer effects of bee venom and its constituent compounds” is the most co-cited reference. The analgesic mechanism of BVT, and its application in arthritis and pain management are the current research hotspots. The treatment of Parkinson disease and cancer with bee venom will become the focus of future research.

Conclusion:

Through bibliometric research, we investigated the overall situation in BVT over the past 2 decades, clarifying the current status, hotspots, and frontier trends in this field. To promote the advancement of BVT and overcome future bottlenecks, it is important for international institutions and research teams to strengthen collaborative exchanges and carry out high-quality, large-sample, multi-center clinical research to further explore standardized treatment protocols and mechanisms of action in BVT, driving its multidimensional development.

1. Introduction

Bee venom therapy (BVT) is a complementary therapy for a variety of diseases by using bee venom, which is produced by the poison glands in the abdominal cavity of female bees.^[1] In the early days, BVT was historically administered via direct bee stings, because bee venom, which is released, will stimulate pharmacological effects in body.^[2,3] Bee venom, as a kind of biological fluid with both advantages and disadvantages, is easy to cause allergic and other adverse reactions through stinging on body, which obviously has safety risks.^[3] At the same time, considering the difficulty of controlling the dose–effect relationship of the application of live bee sting, people learn to extract the effective components of bee venom and apply them to the human body by various methods to achieve anti-inflammatory, analgesic, and other therapeutic effects.^[4]

BVT includes topical application, injection therapy, electrotherapy, and so on.^[1] Topical application refers to the paste product made of bee venom applied to the affected skin, which can promote the healing of various skin diseases.^[3] Bee venom can be injected into certain acupoints or defined location, the former is called bee venom acupuncture.^[5] The method of injection allows the therapist to precisely control the dose of venom, the site and depth of injection, as well as the course and frequency of treatment according to the patient’s condition, under a standard and controlled treatment schedule, so that it is safer and more reliable than traditional bee stings.^[2]

A large number of studies have found that bee venom has anti-inflammatory, antibacterial, antiviral, anti-arthritis, antinociceptive, analgesic, neuroprotective, and anticancer effects, which can be applied to chronic and autoimmune diseases, pain management, and other ailments.^[4,6–8] Further biochemical analysis revealed that melittin, phospholipase A2 (PLA2), histamine, and catecholamines are the critical components of bee venom to exert multiple effects.^[9] However, its safety risks also exist in these compounds, such as melittin, PLA2, and hyaluronic acid, which are highly immunogenic; this is the reason why patients get allergic reactions or even shock during BVT.^[10] Therefore, it is important to perform BVT under the supervision of a professional. Concurrently, researchers are advancing innovative methodologies to optimize venom extraction processes and refine application protocols to minimize allergenic risks while maximizing therapeutic outcomes.

Compared with other alternative therapies, BVT has a clear basis for bioactive substances and a relatively clear mechanism of action. Its theoretical system is established based on modern biomedicine, which makes it verifiable and reproducible. Acupuncture is another common alternative therapy; although it has been found to work by stimulating pathways such as the neuro–endocrine–immune network, the connection between its traditional meridian model and modern physiology is not yet fully understood and still requires further exploration.^[11] Herbal therapy is also different from BVT, which focuses on the purification and research of a single active substance. It pays more attention to the synergistic effect of multiple components; therefore, it is also difficult to accurately define and quantify the specific key molecules, targets, and their interactions.

In recent years, the number of studies on BVT has been increasing, but the use and analysis of the literature in this field are inadequate. This study plans to retrieve literature on BVT published in the Web of Science (WoS) core collection database from 2004 to 2024 and uses software tools such as CiteSpace and VOSviewer to conduct a visual analysis to explore hotspots and frontiers in this field, providing references for future research.

2. Methods

2.1. Search strategy

This study extracted literature from the Science Citation Index Expanded database within the WoS core collection database via the Guangzhou University of Chinese Medicine Library website.^[12] The search formula was TS = (bee venom therapy* OR bee venom acupuncture*) AND DOP = (2004-01-01/2024-04-30). The selected document types included “Article” and “Reviewer article,” whereas the other types were filtered out.

2.2. Data processing

Five hundred studies were retrieved using this search strategy. Two researchers screened the literature independently based on the abstracts and then performed cross-checking. The literature was downloaded after the initial screening, and a second full-text reading screening was performed. If there is any disagreement, negotiate with a third party. There are 493 literatures gathered finally, and these literature records were downloaded and saved as plain text files in the “Full Record and Cited References” format. The literature selection process is illustrated in Figure 1.

Figure 1.

Flowchart of literature screening.

2.3. Date analysis

This study used the CiteSpace (version 6.2. R7) and VOSviewer (version 1.6.20) for bibliometric and visualization analyses. Data were imported into Microsoft Excel 2019 to create a chart.

The text files were imported into CiteSpace to analyze countries/regions, institutions, authors, references, and keywords, and the software parameters are set as follows: Time Slicing was performed from January 2004 to April 2024 (1 year per slice), Keywords were selected for Node Type, Top N% was selected as 50 in Selection Criteria, and Pathfinder was set for Pruning.

After importing text files into VOSviewer, the minimum number of studies for national contribution analysis was set as 3, the minimum number of studies for author contribution analysis was set as 3, the minimum number of collinear of a single keyword was set as 3, and the minimum number of collinear of co-cited literature analysis was set as 20. Through software analysis and calculation, a country cooperation timeline map, co-cited literature cooperation map, author cooperation network map, and keyword co-occurrence map were drawn.

2.4. Ethics statement

The data used in this study are all publicly available secondary data, and do not involve any direct contact, intervention, or data collection with human or animal subjects, nor do they involve any sensitive personal identity information. Therefore, ethical approval was not required.

3. Results

3.1. Analysis of annual publications

There were 493 studies related on BVT, and the number of annual publications is listed in Figure 2. The overall trend can be categorized into 3 distinct stages. In the first stage, from 2004 to 2013, the number of annual publications fluctuated continuously and showed an overall upward trend, with an average of 15 articles per year, representing a period of slow BVT development. In the second stage, from 2014 to 2020, a relatively steady trend was maintained, with an average of 30 articles per year. In the third stage, from 2021 to April 2024, after peaking in 2021, publication volume declined every year. The decrease in the number of publications in 2024 was related to the fact that the data retrieval period for this study was limited to April 30, 2024, and there is typically a delay of 1 to 3 months in the inclusion of literature in the WoS, resulting in incomplete data coverage for the year 2024.

Figure 2.

Annual number of publications on bee venom therapy from 2004 to 2024.

3.2. Analysis of countries/regions

Many countries/regions have participated in the research on BVT; the top 5 ranks belong to South Korea (n = 172), China (n = 84), the United States of America (USA; n = 61), Germany (n = 40), and Egypt (n = 34; Table 1). Asian countries, especially South Korea, China, and Egypt, account for 58% of global publications and are considered core forces in this field. As shown in Figure 3, Croatia, the Netherlands, the USA, and Switzerland are devoted to this field, followed by South Korea, Germany, India, and Egypt, which have been emerged recently. The wider the lines between countries/regions, the closer the cooperation between them. The analysis indicates frequent international cooperation, particularly between the USA, China, and South Korea. In terms of national centrality, China held the first position at 0.28, followed by Germany at 0.27, and the USA at 0.20. This indicates that these countries have achieved breakthrough research in the field of BVT.

Table 1.

Top 10 most prolific and highest centrality of countries/regions related to bee venom therapy.

Rank	Counts	Countries/regions	Rank	Centrality	Countries/regions
1	172	South Korea	1	0.28	China
2	84	China	2	0.27	Germany
3	61	USA	3	0.20	USA
4	40	Germany	4	0.14	Switzerland
5	34	Egypt	5	0.12	Egypt
6	22	Switzerland	6	0.11	Turkey
7	18	Iran	7	0.08	South Korea
8	17	Brazil	8	0.08	France
9	17	Saudi Arabia	9	0.06	Saudi Arabia
10	14	England	10	0.06	India

Figure 3.

Network map of co-authorship and timeline between countries/regions related to bee venom therapy. Node size represents the number of publications by countries/regions, the lines between nodes mean the collaborative relationships, and different colors correspond to different times of entering the research field.

We believe that the traditional medical systems of China and South Korea, which are different from those of Europe and America, and their recognition of traditional culture, are the main reasons why they lead research on BVT. The origin of the BVT can be traced back to remote antiquity in China. Huangdi’s Internal Classic, the earliest medical classic in China, recorded that “the poison of the bee needle can cure diseases.” Based on the cultural recognition of their respective countries’ traditional medicine and the proven clinical efficacy of BVT, China and South Korea have enhanced their investment in traditional medical science and technology, formulated relevant policies and regulations, and accelerated the development of a standardized system to promote the modernization and internationalization of traditional medicine.

3.3. Analysis of institutions

The network map of co-authorship between institutions consisted of 289 nodes and 451 links, with a density of 0.0101, indicating that a total of 386 institutions participated in the research on BVT, which had the closest cooperation and exchanges from 2020 to 2024 (Fig. 4). Kyung Hee University ranked first with 88 papers, followed by the Egyptian Knowledge Bank (n = 34), Korea Institute of Oriental Medicine (n = 32), Seoul National University (n = 25), and Kyung Hee University Hospital (n = 18; Table 2). Overall, institutions in South Korea have the largest number of publications, showing an important position within this field. The highest centrality among these institutions is the Egyptian Knowledge Bank (0.09), showcasing a certain cooperative relationship with others. However, the centrality of each institution is below 0.1, indicating a lack of international cooperation, which limits the development of research in this field.

Figure 4.

Network map of co-authorship between institutions related to bee venom therapy.

Table 2.

Top 10 most prolific and highest centrality of institutions related to bee venom therapy.

Rank	Institutions	Counts	Centrality
1	Kyung Hee University	88	0.02
2	Egyptian Knowledge Bank (EKB)	34	0.09
3	Korea Institute of Oriental Medicine (KIOM)	32	0.01
4	Seoul National University (SNU)	25	0.00
5	Kyung Hee University Hospital	18	0.00
6	Catholic University of Daegu	15	0.01
7	Pusan National University	12	0.01
8	Jeonbuk National University	11	0.00
9	University of Minnesota Twin Cities	10	0.00
10	Chonnam National University	10	0.00

We consider that the low centrality of institutions is mainly attributable to the dominance of regional cooperation among institutions and the lack of international collaboration. In Table 2, although South Korea and its institutions rank high in terms of the number of publications, owing to the large proportion of localized cooperation among institutions, there is regional isolation, which leads to low centrality. Although the Egyptian Knowledge Bank has the highest centrality and ranks second in the number of publications, due to its particularity, it only conducts regional cooperation and has not connected with other countries. China, the USA, and Germany, as countries with top publications and high degree of centrality, have failed to play the role of international cooperation hubs, resulting in a lack of collaboration among international institutions. The fundamental reason for the lack of international collaboration may be related to international cultural differences. This is mainly reflected in Asian countries, especially China and South Korea, which have commonly recognized traditional medical systems, such as acupuncture and acupoints, laying a traditional theoretical foundation for bee venom acupuncture therapy. Although these countries are connecting traditional medicine with mainstream modern medicine, there are still certain cultural barriers between them and the Occident.

3.4. Analysis of authors

The top 10 most prolific authors contributing to the study of BVT are listed in Table 3. The highest number of publications belonged to Roh, Dae-Hyun, with a total of 14 articles, accounting for 2.8%. Ha, In-Hyuk had 13 articles, accounting for 2.6%. A Network map of the co-authorship between authors is shown in Figure 5. Research teams represented by Roh Dae-Hyun, Ha In-Hyuk, and Bae Hyunsu have been formed internationally, and there are some cooperative relationships among them.

Table 3.

Top 10 most prolific authors related to bee venom therapy.

Rank	Authors	Counts	Proportion (%)
1	Roh, Dae-Hyun	14	2.8
2	Ha, In-Hyuk	13	2.6
3	Bae, Hyunsu	12	2.4
4	Lee, Gihyun	12	2.4
5	Lee, Jang-Hern	11	2.2
6	Kim, Me-Riong	11	2.2
7	Park, Kwan-Kyu	11	2.2
8	Lee, Jinho	10	2.0
9	Yoon, Seo-Yeon	10	2.0
10	Lee, Yoon jae	10	2.0

Figure 5.

Network map of co-authorship between authors related to bee venom therapy.

3.5. Analysis of co-cited references

The higher the co-citation frequency, the more critical the reference. Table 4 lists the 10 research papers with the highest co-cited frequencies, published between 2001 and 2012, with Son DJ (2007), Kwon YB (2001), and Lee JD (2005) ranking in the top 3. The document type of these references mainly includes the mechanism of action, review, and experimentation in animals, and the content focuses on bee venom or bee venom acupuncture for inflammatory diseases, pain, and cancer. The paper with the highest co-citation frequency was “Therapeutic application of anti-arthritis, pain-releasing, and anticancer effects of bee venom and its constituent compounds,”^[13] cited 114 times in total. This study describes the signaling pathway and mechanism of bee venom and its compounds in the treatment of diseases, which provides an important basis for follow-up research. “Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses,” a clinical randomized controlled study, which confirms that the analgesic effect of bee venom injection at Zusanli (ST36) and other acupoints is better than that of non-acupoint injection. Figure 6 shows the close relationship between references that have been cited more than 20 times in total. They are roughly grouped into 3 clusters, which are shown in 3 colors on the chart. We used CiteSpace to analyze and identify 25 articles with strong citation bursts of significant impact (Fig. 7), with red stripes indicating the time periods during which the keywords experienced bursts. It can be seen that international research hotspots in the past 5 years have mainly concentrated on the anti-inflammatory, analgesic, and anticancer effects of bee venom-related peptides, compounds, and other components, as well as the exploration of treatment options for bee poisoning.^[2,14,15]

Table 4.

Top 10 co-cited references related to bee venom therapy.

Rank	Frequency	References	Representative author and publication year	Journals
1	114	Therapeutic application of anti-arthritis, pain-releasing, and anticancer effects of bee venom and its constituent compounds	Son DJ (2007)	Pharmacology & Therapeutics
2	81	Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses	Kwon YB (2001)	Pain
3	60	An overview of bee venom acupuncture in the treatment of arthritis	Lee JD (2005)	Evidence-Based Complementary and Alternative Medicine
4	53	Bee venom acupuncture for musculoskeletal pain: a review	Lee MS (2008)	Journal of Pain
5	50	Effectiveness of acupuncture and bee venom acupuncture in idiopathic Parkinson disease	Cho SY (2012)	Parkinsonism & Related Disorders
6	45	The water-soluble fraction of bee venom produces antinociceptive and anti-inflammatory effects on rheumatoid arthritis in rats	Kwon YB (2002)	Life Sciences
7	41	Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-κB through interaction with the p50 subunit	Park HJ (2004)	Arthritis and Rheumatism
8	40	Anitinociceptive effect and the mechanism of bee venom acupuncture (Apipuncture) on inflammatory pain in the rat model of collagen-induced arthritis: Mediation by α2-adrenoceptors	Baek YH (2006)	Brain Research
9	39	Visceral antinociception produced by bee venom stimulation of the Zhongwan acupuncture point in mice: role of α2 adrenoceptors	Kwon YB (2001)	Neuroscience Letters
10	39	Bee venom in cancer therapy	Orsolic N (2012)	Cancer and Metastasis Reviews

Figure 6.

Network map of co-cited references related to bee venom therapy.

Figure 7.

The top 25 references with the strongest citation bursts related to bee venom therapy.

3.6. Analysis of keywords

3.6.1. Co-occurrence network of keywords

Figure 8 shows the co-occurrence network of the keywords in BVT. The frequency and centrality of the top 10 keywords are listed in Table 5, among which the frequency and centrality of “bee venom acupuncture,” “acupuncture,” and “activation” all ranked top 3. Research hotspots in this field have mainly focused on the following treatment methods, document types, and disease types.

Figure 8.

Co-occurrence network map of keywords related to bee venom therapy.

Table 5.

Top 10 keywords and centrality related to bee venom therapy.

Rank	Keywords	Frequency	Centrality
1	Bee venom acupuncture	294	0.29
2	Acupuncture	94	0.25
3	Activation	55	0.16
4	Model	54	0.08
5	Peptide	47	0.12
6	Melittin	45	0.06
7	Arthritis	45	0.11
8	Pain	37	0.07
9	Expression	37	0.13
10	Mechanism	33	0.06

Treatment methods: The high-frequency keywords of treatment methods are “bee venom acupuncture,” “acupuncture,” and some chemical components of bee venom, such as “peptide” and “melittin.” This suggests that research on BVT has been from macro to micro, digging the effective ingredients, so that the treatment and research are more accurate.

Research types: The high-frequency keywords associated with research types are “model,” “activation,” “expression,” and “mechanism.” This indicates that studies mainly focus on applied and basic research, and particularly emphasize establishing models and discussing the mechanism of action.

Disease types: Keywords included “arthritis” and “pain.” Therefore, the mechanism and clinical efficacy of bee venom acupuncture and bee venom in arthritis and pain management are research hotspots in this field.

3.6.2. Clustered network of keywords

The keyword clusters are shown in Figure 9. The network contained 499 nodes and 2713 links, and a total of 8 clusters were obtained and distinguished by different colors. The Modularity Q was 0.4691 (>0.3), and Silhouette S was 0.7906 (>0.5), indicating that the cluster structure was reasonable and credible. The larger the size of the cluster, the smaller the number of cluster ID. Clusters, such as “#0 melittin,” “#2 venom immunotherapy,” “#5 bee venom,” “#6 bee venom immunotherapy, and “#7 immunotoxin,” are related to the treatment method and mechanisms of action; “#1 formalin test” is related to animal experimental models; “#3 parkinsons disease,” “#4 chronic pain,” and “#8 acute renal failure” are related to diseases. Moreover, we further analyzed the evolution of these clusters on timeline, “#0 melittin” and “#6 bee venom immunotherapy” had a longer time span from 2004 to 2024, along with “#3 parkinsons disease” and “#4 chronic pain”, which are active recently (Fig. 10).

Figure 9.

Cluster map of keywords related to bee venom therapy.

Figure 10.

Timeline visualization and clustering analysis of the keywords co-occurrence network.

3.6.3. Keyword burst detection network

The burst times and durations of the top 25 keywords are shown in Figure 11. The keyword with the earliest and longest duration of occurrence was “rat.” The greatest emergences of keyword were “oxidative stress” (5.69), and relevant research is still in progress. In addition, there were some other emergent keywords lasting until 2024, such as “Parkinson’s disease” (2014–2024), “in vitro” (2008–2024), “drug delivery” (2021–2024), “growth-factor” (2008–2024), and “breast cancer” (2022–2024). We can infer that animal or in vitro experiments have been used to investigate the clinical efficacy and mechanism of BVT internationally. Moreover, research on the mechanism of action is still a current research hotspot, and the disease types have mainly focused on Parkinson disease (PD) and breast cancer.

Figure 11.

The top 25 keywords with the strongest citation bursts related to bee venom therapy.

4. Discussion

4.1. Analysis of research status

From 2004 to April 2024, the annual publication of international research literature on BVT can be divided into 3 stages. The number of publications is generally on the rise from 2004 to 2013, and then remains relatively stable for the next 6 years and reaches a peak in 2021, after which it decreases year by year until April 2024. The decrease in the number of publications in 2024 is related to the deadline of data retrieval and the delay of WoS literature entry, but it is a fact that the number of publications declined from 2021 to 2023.

In terms of countries, South Korea and China constitute the leading scientific research forces in this field, among which South Korea occupies the first place with a significant advantage in the number of publications. There is also close collaboration between these 2 nations. In addition, the central influence of China and Germany was relatively large, especially that of China, which showed a dominant position and high international influence in this field. In terms of institutions, research teams represented by Kyung Hee University and Egyptian Knowledge Bank were formed. However, inter-agency cooperation is weak and communication needs to be strengthened. In terms of authors, the 3 research teams led by Roh, Dae-Hyun, Ha, In-hyuk, and Bae, Hyunsu, have published the highest number of papers, and there exists a notable collaborative relationship among them. “Therapeutic application of anti-arthritis, pain-releasing, and anticancer effects of bee venom and its constituent compounds” is the most co-cited reference. This lays an important foundation for further research on the mechanism of action and application of bee venom and its related compounds.

Based on the current situation and keyword analysis of BVT, the decline in the number of publications from 2021 to 2023 might be the result of the combined effects of insufficient international cooperation, reduced resource input, shift in research focus, and lagging clinical transformation. This suggests that research on BVT has entered a bottleneck but is not a signal of the field’s decline. First, due to weak cooperation among international institutions and unbalanced cooperation among countries, the international cooperation network has not been effectively integrated, which has restricted the efficiency of innovation resource integration and knowledge dissemination.^[16] We considered that the fundamental reason for the lack of international collaboration may be related to international cultural differences.^[17] Second, the reduction in resource input is mainly reflected in the fact that after the start of the global COVID-19 pandemic, global research funds have been tilted towards the COVID-19 field.^[18] International organizations as well as government agencies, such as the OECD and the Wellcome Trust, have all mentioned an increase in investment in research funds related to COVID-19 during this period. In contrast, funds for nonemergency fields, such as other infectious diseases and BVT, have relatively stagnated. This affects the investment in and implementation of scientific research. Third, keyword analysis indicates that traditional research hotspots, such as analgesia and arthritis, have approached saturation, but emerging directions, such as the treatment of PD and cancer, are still in the early exploration stage and have not yet formed a complete scale. Currently, the focus of research is on the process of shifting. Moreover, at present, the clinical transformation of various diseases lags behind, and there is a lack of large-scale clinical trials, which hinders the wide promotion and practical application of BVT.^[19] To break through the current bottleneck, it is necessary to systematically optimize the scientific research ecosystem rather than simply expand output.

Therefore, in the future, the BVT field should prioritize the establishment of an international academic alliance to promote multi-institutional cooperation and publish high-quality research results, to overcome the existing limitations of information and resources. Second, increasing financial input to strengthen mechanism and application research in the fields of PD and cancer, carrying out high-quality, large-sample, multi-center clinical research, and focusing on supporting clinical transformation. Moreover, building a consensus knowledge system can promote the formulation of standardized clinical treatment plans for BVT, enhancing the safety and effectiveness of treatment and breaking down cultural barriers. These efforts will help researchers overcome current bottlenecks and promote the multidimensional development of BVT.

4.2. Analysis of research hotspots

Keywords are summarized in this article. Through the analysis of literature keywords and cluster words, the hot spots related to BVT were summarized as follows.

4.2.1. Types of research on BVT

Since the development of BVT, international studies have mainly concentrated on applied and fundamental research. As a common animal model for pain research, the formalin test is widely used in experimental studies. Various animal studies have verified the analgesic effect or mechanism of BVT. However, fundamental research usually focuses on exploring the mechanism of BVT, particularly immunologically mediated analgesic pathways. Through the study of cytokines, signaling pathways, gene expression, and other aspects, the role of bee venom-related chemicals has been elaborated in detail, providing a solid theoretical basis for its clinical application.

4.2.2. Study on analgesic mechanism of BVT

As the main effective component of BVT, bee venom is suitable for pain management, and its mechanism of action has become the focus of current research. It is a kind of animal toxin that contains lots of water-soluble components, which can stimulate peripheral nerves and activate the neurons of the central nervous system.^[20] Studies have shown that in the case of inflammatory pain, bee venom works through stimulating acupoints, which may be achieved by regulating the peripheral β-adrenergic receptors.^[21] In addition, bee venom is also able to relieve pain by participating in the action of δ-opioid receptors and α2-adrenergic receptors. In a study of bee acupuncture for neuropathic pain, it was found that bee venom stimulated acupuncture points to activate the periaqueductal gray matter and locus coeruleus in the brain, which are important opioid and norepinephrine production sites in the central nervous system, so as to achieve analgesic effects.^[20] Although there have been many studies on the analgesic mechanism of BVT in the world, there is currently no systematic theory. Therefore, the analgesic mechanism underlying BVT requires further investigation.

4.2.3. The application of BVT in arthritis

According to literature analysis, pain and arthritis are the focus of BVT, and most of the clinical arthritis will cause protracted pain, such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS).^[22] RA is a chronic inflammatory autoimmune disease, pathologically characterized by persistent synovitis and pannus formation, and these pathological processes drive the erosion of articular cartilage and subchondral bone, finally leading to the destruction of joint.^[23] Research indicates that melittin suppresses lipopolysaccharide-induced expression of d-cyclooxygenase-2, cytosolic phospholipase A2, and inducible nitric oxide synthase, while phospholipase A2 (PLA2) in bee venom modulates T-cell activity.^[24,25] Both components synergistically exert anti-inflammatory effects in RA therapy by targeting distinct molecular pathways. Although BVT has shown certain efficacy in the treatment of arthritis, there is a lack of large-scale, multi-center clinical studies in the world, and a standardized and systematic diagnosis and treatment system has not yet been established. AS, another chronic inflammatory disease, is characterized by inflammation, bone destruction, and heterotopic ossification.^[26] Studies suggest that many inflammatory factors, such as IL-1, IL-6, and TNF-α, are elevated in AS patients, prompting the occurrence and progression of AS.^[27] Bee venom can not only inhibit the production of inflammatory mediators but also hinder the generation of osteoclast-like monocytes by destroying the RANKL/RANK signaling pathway, thus effectively reducing the symptoms of patients.^[23,28]

The increasing clinical demand and reasonable traditional theoretical basis have made arthritis and pain management become the research hotspots in BVT. Aging of the population in East Asia has led to an increase in the prevalence of arthritis. Traditional treatments used, such as long-term nonsteroidal anti-inflammatory drugs, frequently induce gastrointestinal complications, while biological agents impose substantial economic burdens on patients.^[29–31] In contrast, BVT is an inexpensive and effective alternative therapy that can meet the clinical needs of patients. In addition, ancient records documenting the use of bee venom in the treatment of arthralgia within traditional medical systems provide a valuable theoretical foundation for the study of arthritis and pain management. These historical insights have also served as a basis for contemporary clinical research and for further research on modern medical mechanisms.

Park and Shin et al^[16] suggested that bee venom acupuncture could be applied to arthritis, such as RA and knee osteoarthritis, as well as pain syndromes, such as chronic low back pain, and temporomandibular joint disorder. However, most of the guidelines concerning bee venom acupuncture therapy lack detailed descriptions of the treatment plans, and both the evidence level and recommendation level are low or intermediate, indicating that this therapy is advisable or potentially beneficial. These guidelines rely on the preliminary research conducted in South Korea. In conclusion, although BVT has shown certain efficacy in the treatment of arthritis, there is a lack of large-scale and multi-center clinical studies abroad, and a standardized and systematic treatment system has not yet been developed. Therefore, future research should focus on the generation of high-quality evidence and the construction of international standardized treatment programs.

In addition, the occurrence of adverse events related to BVT should be considered. Among the 145 studies,^[32] researchers reported that the median frequency of adverse events related to venom immunotherapy experienced by patients was 28.87%. Compared with normal saline injection, the relative risk of adverse events increased by 261%. To avoid adverse events, patients will be tested for allergies before the first BVT operation. The research and application of nanotechnology provide another promising method for reducing toxic side effects and improving the functional effectiveness of bee venom. In addition, practitioners of BVT should be cautious when applying it in daily clinical practice and should receive education and training to ensure their qualifications for using BVT.

4.3. Future directions of BVT

Through the analysis of co-cited references, keyword timelines, and the burst detection network, it was found that the focus of research has gradually shifted to cancer and PD in the past 3 years.

4.3.1. Research on the anticancer mechanism and application of bee venom

Recent studies have shown that bee venom is valuable for the treatment of cancer, in which PLA2 and melittin exert major effects. The key anticancer mechanism of PLA2 is to activate its cytotoxic effects. While melittin, combined with hormone receptors or gene therapy, can function as a new targeted treatment method for prostate and breast cancer.^[33] In the study of BVT treatment of prostate cancer, it was found that bee venom can inhibit the transcription activity of NF-kB by reducing antiapoptotic gene products, ultimately controlling the activity of cancer cells.^[34] Studies confirm that regulating the dosage and exposure duration of bee venom suppresses metastasis and reduces viability in breast cancer cells.^[35] Moga et al^[19] demonstrated that combining bee venom with chemotherapeutic agents enhances the sensitivity of ovarian cancer cells to conventional chemotherapy, enabling reduced drug dosage and mitigation of adverse side effects. The accumulated evidence suggests that BVT demonstrates significant antineoplastic potential in preclinical models, while its clinical translation remains underdeveloped. Future research should prioritize elucidating the exact molecular mechanisms of BVT in treating tumors and, through systematic pharmacological studies and rigorous clinical trials, promote BVT as a standardized complementary treatment for cancer, ultimately contributing to innovative strategies in cancer care.

4.3.2. The application prospect of bee venom in PD

PD is a degenerative disease of the nervous system; its main pathological manifestations are progressive degeneration of dopaminergic neurons, formation of Lewy bodies, and reduction of dopamine transmitter in the striatum region.^[36] In rotenone-induced PD animal experiments, the study found that bee venom significantly enhanced motor performance in the animals and inhibited rotenone-induced oxidative stress.^[37] Moreover, bee venom reduces the activation of astrocytes, thereby exerting anti-neuroinflammatory effects, and demonstrates neuroprotective effects in the treatment of PD.^[38] Abundant studies have proved the therapeutic potential of bee venom in PD treatment. However, further research is required to elucidate the mechanisms underlying the effects of bee venom in PD therapy, particularly the specific pathways for dopaminergic neuroprotection and antioxidant stress mitigation. Cho et al^[39] found that compared with stable anti-Parkinson drugs, bee venom stimulation of acupoints can improve the symptoms of patients with idiopathic PD to a greater extent. A randomized controlled trial involving 73 patients with idiopathic PD showed that acupuncture and bee venom acupuncture were superior to oral medication in reducing the Unified PD Rating Scale after 12 weeks of treatment, and at 8 weeks after treatment withdrawal, it had a more obvious therapeutic maintenance effect than the sham acupuncture and normal saline injections.^[40] Hartmann and Müllner et al^[41] treated patients with PD by subcutaneous injection of 100 μg bee venom every month for 11 months, and the results did not show significant improvement in any symptoms of patients. However, the authors believe that increasing the frequency of administration and the individual dose may improve the efficacy of bee venom treatment. Additionally, large-scale and multi-center clinical trials are needed to comprehensively evaluate the efficacy of bee venom in PD management, thereby providing a stronger theoretical foundation and practical guidelines for clinical applications.

5. Limitations

This study has some limitations. First of all, this study only used the WoS Core Collection database. Although non-English literature was not actively excluded, the limited coverage of this database for regional journals, such as Chinese and Korean native journals, may have resulted in some high-quality regional research achievements not being included. Second, to ensure the quality of the literature, this study also excluded gray literature, such as meeting abstracts and letters, which might result in the absence of the latest clinical protocols published in such articles.^[42] In addition, we may overlook the citation bias inherent in the bibliometric tools. For instance, CiteSpace tends to magnify high-impact journal papers while neglecting important but low-cited studies. However, ultimately, the above limitations have no substantial impact on the overall conclusion of this study, especially the dominant position of China and Korea, and the core research on arthritis, but may weaken the trend strength of emerging fields, such as PD.

6. Conclusion

This study utilized 2 professional bibliometric tools, CiteSpace and VOSviewer, based on the authoritative database WoS, to conduct a multi-dimensional analysis of global BVT research from 2004 to 2024 for the first time. It visually presents the research status, hotspots, and future trends of BVT over the past 20 years. While ensuring the comprehensiveness and reliability of the analysis results, it fills a long-standing gap in the lack of systematic literature analysis in this field. Moreover, in response to the current shortcomings, such as insufficient international cooperation, reduced resource input, lagging clinical transformation, and obvious disciplinary barriers, this study points out the future direction of international research development and clinical needs. This research specifically focused on its clinical applications in pain management and arthritis while systematically exploring its multifaceted analgesic mechanisms. It is anticipated that an international academic alliance in the field of BVT will be established in the future, accompanied by increased financial investment. This would facilitate more clinical translational research, promote the development of standardized treatment protocols for BVT, and provide robust evidence to support the broader promotion and application of BVT, thereby advancing scientific and global development.

Author contributions

Conceptualization: Dekai Zhou.

Formal analysis: Kezhuo Yan, Haipeng Lu.

Methodology: Dekai Zhou.

Project administration: Wanglong Chen.

Software: Dekai Zhou.

Supervision: Wanglong Chen.

Visualization: Kezhuo Yan.

Writing – original draft: Kezhuo Yan, Haipeng Lu, Zhiqing Liao, Chunyu Cai, Chenlu Hu.

Writing – review & editing: Kezhuo Yan, Dekai Zhou, Weichang Huang.