Published studies from January 1, 2002, to December 31, 2021, related to BBR and tumors were collected from the Science Citation Index Expanded (SCI-E) of the Web of Science (WoS) Core Collection (WOSCC) of Clarivate Analytics. To guarantee the reliability and accuracy of the findings, we performed pertinent pretests and improved the retrieval method. The retrieval method is illustrated in Figure 1. We used the WoS engine to search for terms related to BBR and cancer that were obtained from the Medical Subject Headings (MeSH) in PubMed. The search formula was TS = (Berberine or Umbellatine) and TS = (Tumor or Neoplasm or Tumors or Neoplasia or Neoplasias or Cancer or Cancers or “Malignant Neoplasm” or Malignancy or Malignancies or “Malignant Neoplasms” or “Neoplasm, Malignant” or “Neoplasms, Malignant” or “Benign Neoplasms” or “Benign Neoplasm” or “Neoplasms Benign” or “Neoplasm Benign”). Only publications written in English were included. The reasons for exclusion from the study were 1) no connection between BBR and tumors of any kind; 2) meeting abstract, correction, editorial material, proceeding paper, retracted publication, book chapters, early access, retraction, etc.; and 3) publications in a language other than English. A total of 1,368 papers were obtained.

All retrieved documents were used for the bibliometric analysis. We extracted information including titles, annual publications, countries and institutes, authors, references, keywords, and scientific cooperation analysis. Data were independently extracted from a set of articles by TY and YRZ. SP-H mediated the outcomes if a disagreement arose.

We used CiteSpace (version 6.3. R3), VOSviewer (version 1.6.18), Bibliometrix (version 3.1.4), R language (version 3.6.3), and Microsoft Excel 365 for data analysis and presentation.

CiteSpace, developed by Prof. Chao-mei Chen, is a bibliometric mapping analytical tool used worldwide, most predominantly in China (Qin et al., 2022). It is a free program for analyzing, identifying, and visualizing trends and patterns in scientific literature and was chosen as the analysis target (Pan et al., 2017). In our investigation, the specifics of the CiteSpace settings were as follows: time slices of 1 year each were taken from 2002 to 2021. The links (strength: cosine; scope: inside slices) and term sources (title, abstract, author keywords, and keywords plus) were set to the default values. Items with a g-index citation or occurrence were selected for this study. Links that were not necessary were removed using Pathfinder.

VOSviewer, developed by van Eck and Waltman, creates visual network maps of scientific information, including bibliometric network analysis (van Eck and Waltman, 2010). We used VOSviewer to create network, overlay, and density visualization maps. We chose the “full counting” method for our analysis. For keywords and co-cited journals, the thresholds for the minimum numbers were set at 100 and 5, respectively. Keywords or co-cited journals are displayed as nodes in the form of a network through a visualization diagram.

Visualization of the annual publication numbers; country, institute, author, and journal rankings; cited reference bursts; and most globally and locally cited Local Cited Documents, was performed using Microsoft Excel 365. Additionally, we performed a descriptive study of writer output over time and keyword evolution in Bibliometrix (Cheng et al., 2022). Bibliometrix (https://www.bibliometrix.org) is an open-source instrument for quantitative scient-metric research. Machine-learning software was used to evaluate the distribution of each component examined in the bibliometric investigation. The variables were annual scientific production, average citations per year, most impactful journals by H-index or total citations (TC), top journals’ production over time, most relevant authors, most globally and locally cited documents, most pertinent affiliations, country-level scientific output, international collaboration network, country of origin of the corresponding author, top producing nations over time, historical direct citation network, most widely cited publications, most pertinent keywords, and keyword cluster analysis. Impact factor (IF) and partition information for the journals referred to the “Journal Citation Report (JCR) 2022.” These analytical methods offer unbiased and varied viewpoints on the function of berberine in tumor formation. The variables are presented as numbers and percentages in the descriptive study. p-values were not reported because no comparisons were made.

We assessed the historical development process, current research conditions, and forecasted future trends in development by statistically analyzing the general usage of BBR pharmacological functions in the number of publications over time.

We counted the number of papers related to “berberine and tumors” from 1972 to 2021 and collected 1,587 articles for bibliographic records from the WOSCC. Ultimately, 1,368 articles were eligible for the next stage of analysis based on the exclusion criteria of publication time, document type, and language. Figure 2A shows the number of articles published each year and the cumulative number of articles published from 2002 to 2021. The overall trend has increased over the past 20 years. The greatest number of papers was published in 2021, with 180 research articles. The exponential curve equation for the rise in literature production was y = 11.819e^0.2604x, which conforms to Price’s law. The simulation curve had a relatively strong coefficient of determination (R ² = 0.9543), which fitted the annual literature growth trend well. Based on this curve, we predicted that the number of annual articles will steadily increase, indicating increased interest in research on BBR and tumors.

Statistics on the research countries reporting on publications related to “berberine and tumors” showed the stages of BBR pharmacology development in each country and made comparisons easier. According to WoS, many countries have participated in research in the last 20 years. Table 1 lists the top 10 productive countries. China had the most publications (783 articles), accounting for 57.24% of the total, followed by the United States and India (142 articles each, accounting for 10.38% each, respectively), South Korea (n = 97), Italy (n = 61), Iran (n = 60), Japan (n = 42), Egypt (n = 30), Germany (n = 26), and Poland (n = 24).

Publications from China ranked first in total number of citations, but the average number of citation per paper was very low, only 30.14%, compared to the top 10 countries. Although the number of articles published by Germany was limited compared to China, the average citation per article ranked second among the top 10 countries. This finding suggested that the publications were of very high quality and had certain reference values. The H-index is a mixed quantitative indicator that considers both the number of posts and the required number of citations and can be used to identify influential researchers (Hirsch, 2005). China’s researchers had the highest H-indexes, demonstrating the significant impact of their publications. After 2008, most global publications came from China. Figure 2B shows the total number of papers published worldwide from 2002 to 2021.

Using an online bibliometric analysis platform, we evaluated the significance of nations in the visualization of cooperative networks. Katz and Martin, two scientists, defined scientific cooperation as the study of academics collaborating to create new scientific knowledge, known as scientific collaboration (Katz and Martin, 1997). Figure 3A shows partnerships between countries, among which articles from China showed the most aggressive cooperation with other countries; most often between China and the United States. We conducted a visual analysis using VOSviewer (Figure 3B). The circles in the map represent countries and the lines indicate the connections between them. The larger the area of the circle, the larger the contribution of these countries to this field. We found that China made significant contributions to research on BBR and cancer. A density map can be used to determine the number of publications in each nation. The lighter the color, the greater the number of publications. The density map was used to determine the number of publications in each nation (Figure 3C ). As shown in Figure 3C, China had the highest number of publications. Figure 3D shows that American publications were generally concentrated before 2016, whereas Chinese, Indian, Italian, and Iranian articles were concentrated after 2016.

The top 10 productive institutes are listed in Table 2. China Medical University (Taiwan) and Sun Yat-Sen University (China) had the most publications, with 36 articles each. China Medical University (Taiwan) showed the highest total number of citations (1,417) and H-index (21), with an average number of citations of 39.26, demonstrating a high level of acclaim for its articles. We used VOSviewer to depict the cooperation between institutes in Figure 4A. Figure 4B shows each institute’s cooperation timeline from 2002 to 2021; the node color on this map corresponds to each institute’s cooperation respective average appearing year (AAY). Jilin University and Mashhad University of Medical Sciences had relatively fresh entries compared to the nations shown in purple, such as China Medical University (Taiwan), according to the color gradient in the lower right corner.

The top 10 authors in terms of the number of articles in the past 20 years are listed in Table 3. Y. B. Feng of the University of Hong Kong, was the most prolific author (21 articles) and also received the highest number of total citations (1,281) and had an H-index of 17, demonstrating his significant contributions to the field. O Paolo from Naxospharma published 17 articles, while L Paolo and K Gopinatha Suresh (Indian Institution of Chemical Biology) both had H-index values of 12.

The top 10 journals according to the number of publications are shown in Table 4 and Figure 5. The top 10 journals published 252 papers, or 18.42% of all the included publications. Frontiers in Pharmacology (IF = 5.9879) was the most popular journal with 29 articles, followed by Molecules (IF = 4.9269) with 28 articles. PLOS One (IF = 3.7521) was the most frequently cited journal (1,388 citations). The distribution of journals across fields, evolution of citation trajectories, and drift of scientific research centers can be displayed using the dual-map overlay of journals (Chen and Leydesdorff, 2014; Zhang et al., 2021a). In our dual-map overlay analysis (Figure 5E), the left side shows the distribution of the journals where the citing documents were located, representing the main disciplines of science mapping, while the right side shows the distribution of the journals corresponding to the cited literature, representing which disciplines were mainly cited by science mapping. The results showed that research related to BBR and tumors was mainly associated with the areas of molecular/biology/immunology and was often cited by molecular/biology/genetics researchers.

We quantified the knowledge and development of research on a particular topic by evaluating the significant nodes and clusters in the co-cited reference network (Yin et al., 2022). We used CiteSpace to create a timeline-visualized diagram network map of the co-cited articles, which was divided into 19 clusters (Table 5). The co-cited reference network is shown in Figure 6A, in which the node size is the proportion of the research frequency, color is the proportion of the time slice, and the connections are represented by lines. We further conducted cluster analysis on these co-cited articles based on the keywords in those articles (Figure 6B). By removing phrases from the titles of the cited publications, we identified the main research hotspots. Figure 6C shows a timeline of references in the field of BBR and tumors, as determined by CiteSpace. We observed a shift in the focus of research over time. The development of clusters 2 (interleukin 1 beta), 9 (structure-based molecular modeling), and 10 (herb) occurred the earliest, indicating that early research focused more on BBR structure and pharmacology. Clusters 1 (Daxx), 6 (prostate cancer), and 7 (tumor necrosis factor-alpha) occurred between 2007 and 2011, indicating a focus on the anti-cancer molecular mechanism of BBR. Clusters 15 (carbohydrate), 3 (photodynamic therapy), 4 (non-small cell lung cancer), and 11 (gut microbiota) are current research hotspots. Figure 6D shows the top 10 references with the strongest citation bursts, highlighting their significance in the fields of BBR and tumor-related research. In addition, we list the total citations of articles and local citations of articles in Tables 6 and Table 7, respectively.

Keywords are generally regarded as a significant index to reflect research frontiers and hotspots in a certain topic (Zhong And Song, 2008; Wu et al., 2021). We produced a map showing the co-occurrence of keywords using VOSviewer. The cooperation network (Figure 7A) clearly shows keywords changing from 2002 to 2021. At present, the keywords are main focused on “berberine”, “apoptosis” and “cancer”, and so on. Figure 7B shows the evolution of keywords in a typical publishing year. Initially,research on BBR mainly focused on “alkaloid”, and “tumor necrosis factor-alpha”; then, the research keywords shifted towards “prostate cancer”, “rapamycin” and “p53”; finally, the most recent keywords have become more diverse, with topics including “mechanism”, “cancer” and “gut microbiota”, and so on. Figure 7C shows the frequency of keywords in different time periods, the larger the size of the node, the higher the search frequency. In conclusion, “apoptosis”, “non-small cell lung cancer”, and “gut microbiota” were the most frequently searched terms.

As shown in Figure 6B, BBR has been used in the treatment of lung cancer (#13), prostate cancer (#6), and non-small-cell lung cancer, and has been a research hotspot in recent years (Figure 6C). The mechanisms of action of BBR in cancer have also been studied and mainly consist of inhibiting migration and invasion, inducing apoptosis, arresting the cell cycle, inhibiting proliferation, and promoting autophagy in tumors.

Figure 6 and Figure 7 list several conditions that can be regulated by BBR, including non-small-cell lung cancer, breast cancer, colorectal cancer, gut microbiota, and photodynamic therapy. Among these, the application of BBR in cancer has been the focus of research in recent years. The results are summarized in Table 8.