Plant extracts with antioxidant and hepatoprotective benefits for liver health: A bibliometric analysis of drug delivery systems

Abstract

BACKGROUND

The rising global burden of liver diseases, such as non-alcoholic fatty liver disease and liver fibrosis, has necessitated innovative therapeutic approaches. Plant-based therapies, recognized for their anti-inflammatory and antioxidant properties, have shown promising effects. However, poor bioavailability limits their clinical application.

AIM

To map global research trends, key contributors, and emerging themes in plant-based therapies combined with advanced drug delivery systems for liver health.

METHODS

Using the Scopus database, 645 documents were retrieved and analyzed using bibliometric tools Biblioshiny and VOSviewer. Analysis focused on publication trends, geographical contributions, and advancements in drug delivery technologies, including nanoparticles, liposomes, and polymeric micelles. Metrics such as publication growth rate, authorship collaboration, and thematic clustering were assessed.

RESULTS

The dataset spans 43 years (1981-2024), with an annual growth rate of 11.09% in the number of publications. Research output is dominated by China (33%), followed by the United States (24%) and India (18%). Collaborative studies accounted for 24.34% of publications, with an average of 5.81 co-authors per document. Key innovations include nanoparticle encapsulation of curcumin and silymarin, improving bioavailability by up to 85%. Highly cited studies demonstrated the antioxidant, anti-inflammatory, and anti-fibrotic properties of these compounds. For instance, curcumin nanoparticles showed a 70% improvement in solubility, and silymarin liposomal formulations enhanced therapeutic efficiency by 62%. Thematic analysis revealed a transition from basic clinical observations to molecular and pharmacokinetic research, with a focus on oxidative stress mitigation and hepatoprotection.

CONCLUSION

This study highlights the growing synergy between plant-based therapies and advanced drug delivery systems, with significant contributions from Asian and Western countries. Future efforts should prioritize clinical trials, standardization of plant extract formulations, and interdisciplinary approaches to maximize therapeutic outcomes. The findings provide a foundation for integrating plant-derived compounds into evidence-based hepatological therapies, addressing critical challenges in bioavailability and safety.

Key Words: Liver health; Plant extracts; Drug delivery; Pharmacokinetics; Hepatoprotection; Bioavailability; Bibliometric analysis

Core Tip: The increasing prevalence of liver diseases requires innovative treatments. This bibliometric study maps global research on plant-based therapies integrated with advanced drug delivery systems, analyzing 645 publications from 1981 to 2024. Key innovations, such as curcumin and silymarin nanoparticle encapsulation, significantly enhance bioavailability and therapeutic efficacy. The study highlights global research trends, major contributors, and evolving themes in hepatoprotection. Findings emphasize the need for clinical trials and standardization to bridge the gap between experimental research and clinical application, advancing plant-derived therapies for liver health.

INTRODUCTION

Liver disorders affect millions of people every year and account for 4% of all deaths worldwide (1 out of every 25 deaths)[1]. These afflictions vary in severity, ranging from acute hepatitis and liver fibrosis to chronic diseases such as cirrhosis and non-alcoholic fatty liver disease (NAFLD)[1-3]. These conditions often lead to severe complications, including liver failure and hepatocellular carcinoma[4,5], which together contribute to high morbidity and mortality rates worldwide[6]. Traditional approaches to treating liver diseases comprise pharmacological and surgical techniques[7,8] which have several inherent drawbacks, including serious side effects and poor to moderate efficacy in advanced stages of liver disease, as well as relatively high costs[9,10]. These limitations have led to a compelling need to explore safer, more effective, and cost-effective therapeutic alternatives. This has increased interest in plant-derived natural compounds as complementary or alternative therapeutic options for managing liver diseases.

There is increasing interest in the application of plant-derived natural compounds in the treatment of liver diseases[11,12]. Among plant phytochemicals[13], polyphenols, flavonoids, and alkaloids have received attention for their antioxidant and therapeutic properties and are therefore promising entities for new hepatoprotective therapies[14,15]. These bioactive compounds have therapeutic benefits and are also widely available, relatively safe, and have aligned with an increasing demand for natural health solutions[16]. In particular, antioxidant properties may be beneficial in mitigating oxidative stress, while antibacterial effects may help manage infections associated with liver complications[17-19]. However, problems such as poor solubility, rapid metabolism, and low bioavailability when administered in conventional forms hinder the potential for clinical application of these plant-derived compounds[20].

Advances in drug delivery systems for plant-based therapies in liver disease

While plant extracts hold great promise in treating liver diseases[21] due to their properties as hepatoprotective agents[22] with antioxidant and anti-inflammatory actions, their use is hampered by their bioavailability, stability, and delivery to liver tissues[23,24]. In light of these challenges, advanced drug delivery systems that enhance the pharmacokinetic profiles of natural compounds and direct the action at the specific site have been developed[25,26]. This chapter reviews recent advances in drug delivery that enhance the use of plant extracts for treating liver disease. These include nanoparticles, liposomes, polymeric micelles, and nanoemulsions[8].

Nanoparticles for enhanced bioavailability and liver targeting: Nanoparticles protect plant extracts from degradation and target delivery to the liver[27,28], enhancing bioavailability and potential therapeutic effects[29]. Polymeric nanoparticles, particularly biodegradable polymers like polylactic-co-glycolic acid (PLGA), are used to prepare polymeric nanoparticles[30] that ensure controlled release and sustained therapeutic effects specifically to the liver[31,32]. For example, silymarin-PLGA nanoparticles have improved its bioavailability[33] and antioxidant activity[34,35]. Thus, the therapeutic activity of the compound extends to liver cells[36]. Lipid nanoparticles, namely solid lipid nanoparticles and nanostructured lipid[37] carriers, can be used to deliver hydrophobic plant extracts to the liver[38,39]. In this application, encapsulation of compounds like curcumin in lipid nanoparticles increased its solubility and bioavailability and protected hepatocytes from oxidative liver damage[40,41]. Nanoencapsulation refines targeting by exposing the nanoparticle surface to the recognition moieties of liver cells[42,43], therefore enhancing the therapeutic exposure of drugs such as quercetin and resveratrol[44]. These formulations demonstrate extended antioxidant and anti-inflammatory activities.

Liposomal encapsulation for liver-specific delivery: Liposomes can encapsulate both hydrophobic and hydrophilic plant extracts as a biocompatible phospholipid bilayer, thus elevating the bioavailability and pharmacokinetics of natural compounds[45]. Their stability and bioavailability can be improved through encapsulation by liposomes, as it protects phytochemicals from degradation and enables improved absorption and bioavailability[46,47]. For example, liposome encapsulation of curcumin[48] enhances its therapeutic effectiveness, making it a potential treatment of liver fibrosis and NAFLD[49,50]. Through liver-specific modifications via surface modification of liposomes with specific ligands[51], compounds like silymarin can be delivered to the liver in a targeted fashion[52]. It could potentially reduce off-target effects and increase concentrations within the liver, ensuring safety in chronic therapies.

Polymeric micelles for enhanced solubility and controlled release: Polymeric micelles are amphiphilic block copolymers[53] that increase the solubility and stability of insoluble plant extracts[54,55] against hydrophobic environments and are linked to higher therapeutic efficacy in liver treatments[56,57]. Polymeric micelles increase the solubility of hydrophobic hepatoprotective agents such as berberine and quercetin in water[58-60]. Compounds with better solubility increases their absorption time, thereby increasing the therapeutic activities against oxidative damage to the liver[61,62]. Polymeric micelles provide controlled and sustained release profiles that retain therapeutic levels of active compounds over extended periods[63,64]. For example, with quercetin-loaded micelles, there is some evidence of longer-lasting effects on antioxidant activity[65,61], thus sustaining its hepatoprotective properties.

Research gaps and rationale of this study

Despite increasing interest in phytotherapy for liver diseases and advances in drug delivery systems, there is still a lack of understanding of these fields. This field of research is comprised of two main categories: (1) the pharmacological activity of a liver-protective plant extract; and (2) the design of drug delivery mechanisms. However, very few investigations have optimized these advanced delivery systems[66], like nanoparticles, liposomes, and polymeric micelles, to augment the pharmacokinetics and bioavailability of plant-based compounds within liver-targeted applications[67]. Indeed, such a limited focus has resulted in an incomplete view of how best to harness plant extracts for hepatoprotective efficacy[68] in all cases of liver diseases, including NAFLD, liver fibrosis, and cirrhosis. While plant extracts are widely known to possess antioxidant and hepatoprotective activity[69,70], systematic inputs on leveraging those properties through the use of patient-friendly and drug-delivery strategies are scarcer[71]. Without a well-organized understanding of research trends, key contributors, and thematic developments at the intersection of plant-based therapies and drug delivery for liver health, future research in this area risks becoming directionless and missing valuable opportunities[72].

This bibliometric analysis fills this research gap by mapping and analyzing scholarly contributions, trends, and collaborations in this multidisciplinary field. By providing a detailed overview of publication patterns, influential authors, research hotspots, and emerging themes, this study aims to highlight important insights and inform future research. This would enlighten both about current advancement and lead to areas of unmet needs, as well as directions to consider while optimizing the plant-based drug delivery systems tailored for improving liver health, hence being supportive of better and more targeted therapeutic strategies.

MATERIALS AND METHODS

Database selection

In the current study, SciVerse Scopus was used to accomplish the study's objective. Scopus is larger than the Web of Science and has over 23000 indexed journals in every scientific field[73,74] and is 100% inclusive of MEDLINE. Scopus offers both a basic and an advanced search in which complex and long search queries can accomplish the objective with high validity. Scopus allows a search using words in titles, titles/abstracts, or journal names, author name, or author affiliation. Hence, Scopus was used for the literature search and analysis.

Search strategy

The search strategy was designed to specifically focus on liver health, plant-based therapeutic agents, and advanced mechanisms for drug delivery. Streamlining the keywords into an iterative process helped to filter it to one that was precise but exhaustive.

Keyword identification: Central concepts associated with liver health, plant extracts, and drug delivery were identified. Common terms in the field, literature, and consulting domain experts were consulted to define specific terms and synonyms. For example, under liver health, terms like "liver disease", "hepatoprotection", "NAFLD", and "cirrhosis" were collected to cover a range of liver conditions. For plant-based compounds, search terms like "plant extract*", "herbal extract*", "botanical", and "phytochemical*" were applied to target research on natural or herbal compounds. Under drug delivery, the search terms ranged from bioavailability, pharmacokinetics, and nanoparticle*, to encapsulation, which represent various delivery methods that can enhance the efficacy and targeting of therapeutic agents.

Iterative refinement: The number of search trials was multiplied to refine keywords. Variations and additional keywords were screened and reviewed for relevance and scope. The overly general terms that returned irrelevant hits were eliminated, while more specific terms were added to include niche research.

Final query: The following is the final Boolean search query developed thorough experimentation and refinement. It employs terms that embrace liver health, plant-based therapies, and advancements in drug delivery.

[TITLE-ABS-KEY ("liver health" OR "liver disease" OR hepatoprotection OR hepatotoxicity OR "fatty liver disease" OR "hepatitis" OR "liver fibrosis" OR "cirrhosis" OR "non-alcoholic fatty liver disease" OR nafld OR "alcoholic liver disease" OR "liver abscess") AND TITLE-ABS-KEY ("plant extract*" OR "herbal extract*" OR botanical* OR "natural compound*" OR phytochemical*) AND TITLE-ABS-KEY ("drug delivery" OR pharmacokinetics OR bioavailability OR nanoparticle* OR encapsulation)].

This search query was designed to return recent studies at the crossroads of liver health, plant-derived therapeutic agents, and drug delivery technologies. Because it restricts the search to titles, abstracts, and/or keywords, it ensured that the retrieved articles were closely aligned with the study objectives. A total of 645 studies were returned and included for consideration of presenting a comprehensive view of the research field.

Extraction and inclusion criteria of data

All metadata of 645 articles from the Scopus database were extracted. The titles, abstracts, keywords, authors, publication years, and journal sources were extracted by the Biblioshiny auto-analyzer tool and validated by manual screening. No articles were excluded from analysis because the purpose was to capture as much relevant research as possible. The articles retrieved during the search were included in the study, constituting the inclusion criteria. Articles of all types and languages were included in the study to effectively capture each publication or idea. The full dataset was then prepared for bibliometric and thematic analysis.

Bibliometric analysis tools: Biblioshiny and VOSviewer

Analysis was performed through Biblioshiny[75] and VOSviewer (https://www.vosviewer.com/) to explore patterns of publication, research impact, collaboration patterns, and thematic clusters in the dataset.

Descriptive analyses of Biblioshiny were applied toward exploring publication growth rates, top authors, institutions, countries, and journals. This analysis was used to explore the volume of research output, key contributors, and the overall impact of the field. With the VOSviewer tool, visual network maps illustrating co-authorship, co-citation, and keyword co-occurrence patterns were graphed. The maps indicated collaborative networks in authors, influential works, and repeated research themes and, as such, gave a visual overview of the field's structure and focal points.

Data analyses and visualization

Analyses were performed through multiple layers of the dataset, allowing for investigation into publication trend patterns, authority sources and authors, thematic clusters, and collaborative networks. These different types of analysis further enabled distinct views of the dataset, presented in greater detail below.

Overview: This preliminary analysis provided general statistics on the dataset regarding the total number of publications, the period covered, average citations per document, and the geographic distribution of publications. As such, this overview helped create a basic understanding of the scale, scope, and impact of research on liver health, plant-based compounds, and drug delivery.

Sources analysis: Sources analysis identified the most dominant journals and publication sources that have a great impact on the field. It involves the application of metrics including the number of articles, total citations, and h-index values (a metric that measures a researcher's productivity and impact based on the number of publications and frequency of citations) of each journal to identify the sources that have had the greatest impact. Analysis was performed on influential journals in which research involved liver-targeted plant-based therapies and drug delivery, directing readers to important sources with the most credible results.

Author analysis: Author analysis helped reveal the most active and leading quoted researchers in this field. Key metrics considered included the number of publications per author, total citations, and corresponding h-index values. This analysis identified the most influential researchers who have been prolific in publishing works within the liver health and drug delivery field and in frequent coauthorship. Co-authorship network visualizations illustrate the relationships among authors in of collaborative clusters and leading research groups.

Document analysis: Document analysis was performed to identify the most cited studies in the dataset. It provided critical information that connected kernel articles and identified the highest impact studies guiding the research paradigm shift in liver disease, plant-based therapies, and drug delivery technologies. Identification of the most highly cited documents allowed for outlining of key works that established the basic findings and methodologies in the field.

Clustering analysis: Related studies with keyword co-occurrence and co-citation patterns were clustered into themes. The clusters are different themes within the dataset, ranging from "antioxidant and antibacterial applications of plant extracts" to "enhancement of pharmacokinetics and bioavailability" as well as "nanoparticle-based liver-targeted drug delivery". This process unveils subfields and dominant themes within the data, hence clarifying the way in which the research in this area is organized.

Conceptual structure analysis: A conceptual structure was mapped by co-word analysis that illustrated the relationships of frequently used words in the dataset. It showed the ability to detect major topics and subtopics within the literature, thus making well-established areas and emerging areas apparent. The conceptual map provided a thematic overview of the subject matter and demonstrated how closely related topics like liver protection, phytochemicals, and bioavailability enhancement were.

Social structure analysis: Social structure analysis of co-authorship networks allowed for analysis of the patterns of collaboration in a network that mapped relationships between authors, institutions, and countries. International and institutional partnerships have been identified through this type of analysis by highlighting partnerships that play a key role in leadership contributions for health-related advancements in liver diseases and plant-based drug delivery systems. These visual analyses provided a multi-dimensional view of the research landscape, including trend patterns, key contributors, thematic concentrations, and collaboration networks. They therefore supported a panoramic view of scholarly activity concerning plant-based therapies for liver health and innovative drug delivery systems in a sense that an advance could be shaped into identifying potential future directions of research.

RESULTS

Overview of the data

The bibliometric dataset spans a total of four decades, from 1981 to 2024[76,77], detailing this period-spanned research on liver health, plant extracts, and drug delivery systems. The dataset included 645 documents in total, while the source journals and publication outlets were drawn from 345 different journals, representing a diverse and multidisciplinary interest in the study. As far as research activity is concerned, this field has experienced a gradual annual growth of 11.09%, which points to the raised scientific interest in natural compounds for liver diseases and advanced delivery methods. These data are summarized in Table 1.

Table 1 Summary of bibliometric analysis metrics for research on liver health, plant extracts, and drug delivery.

Metric	Value
Timespan	1981-2024
Sources	345
Documents	645
Annual growth rate (%)	11.09
Authors	3091
Authors of single-authored	28
International co-authorship (%)	24.34
Co-authors per document	5.81
Author's keywords (DE)	2031
Document average age (years)	5.8
Average citations per document	41.14

This aggregate literature comprised 3091 authors with only 28 authors who have single-authored works, which points to strong trends toward collaboration. An average number of 5.81 co-authors per document suggests high collaboration in the field, reflective of its interdisciplinary nature. International co-authorship accounted for 24.34% of the publications, indicating a considerable amount of global collaboration and knowledge exchange.

The dataset consisted of 2031 unique author keywords. This established the richness and diversity in terms of topics and specific terms within this research space. The average age of the documents was 5.8 years, which established that this was indeed a living field constantly in development and that much of the research in this field was quite recent. On average, each document had 41.14 citations, demonstrating the impactful nature of the studies.

Upon carefully screening the articles, we identified a total of 472 non-human studies, namely 231 animal studies and 268 plant studies or a combination of two. Moreover, there were 308 human-based studies that investigated the use of plant extracts or products.

Figure 1 represents the annual scientific production across more than four decades of the research area on liver health, plant-based extracts, and drug delivery systems from 1981 to 2024.

Figure 1 Annual scientific production (1981-2024).

Trends in the number of publications show that there has been many documents published over time, but with a generally low and stable output until about 2005. After 2005, output gradually increased and has been at an increased rate since 2015. The trend of publication cases, particularly since 2018, reveals high interests and with increased research activities. The peak in 2024 indicates that this is an active area of expanding research focus, potentially spurred by growing interest in natural compounds for liver health and developments in drug delivery technologies.

The average annual citations for articles on themes like liver health, plant-derived extracts, and drug delivery were studied from 1981 to 2024[78]. The number of citations variably fluctuated, sometimes spiking within average citation levels. One major increase occurred around 2000[79,80], and another one at approximately 2018[81-83], indicating that perhaps especially impactful studies were published during these periods, which were heavily studied by academia. Citation bursts are also seen with the subsequent dips in the overall trend, a result of the introduction of new studies or a shift in the scientific direction of the subfield. The recent decline is likely a lag in citations of new research articles, which need more time to accumulate citations. This therefore highlights the persistence and the changing dynamics of influence of key publications over time in such a quickly evolving research area.

Figure 2 shows a three-field plot that illustrates the university-author-keyword associations made in the fields of liver health, plant extracts, and drug delivery. The institutions that play a major contributing role are shown in the left column. Prolific authors are in the middle column, and the most frequent keywords are in the right column to illustrate which of the authors' work focuses on the theme.

Figure 2 Three-field plot showing university affiliations, authors, and research keywords.

Several Chinese universities performed the most research in this area, such as Heilongjiang University of Chinese Medicine, Nanjing University of Chinese Medicine, and Chengdu University of Traditional Chinese Medicine. This demonstrates that research is highly concentrated on traditional medicine and natural compounds within China. The top authors are Li X, Li et al[84], Zhang L, Yang Y, etc. However, most of them are affiliated with major Chinese Universities. These authors have made good contributions to the research of natural compounds and liver health because they are related to many keywords in the plot[85].

Recurring keywords can often be seen from the perspectives of pharmacokinetics, pharmacology, phytochemistry, toxicity, and hepatotoxicity, which are the major research themes in this discipline. Other recurring keywords like oxidative stress, anti-inflammatory, hepatoprotection, nanoparticles, and particular types of phytochemicals such as curcumin, and silymarin, reflect the interest in liver protection, bioactivity, and drug delivery. Many of the authors connected with Chinese universities are related to the keywords "phytochemicals", "toxicity", and "nanoparticles", leading to an implication of thematic emphasis on pharmacokinetic and hepatoprotective properties of natural compounds, as well as their delivery by advanced drug systems.

Source analysis

Figure 3 shows the most relevant sources for research on liver health, plant extracts, and drug delivery. The highest number of publications comes from the Journal of Ethnopharmacology with 48 publications, consistent with the journal's focus on traditional medicine and natural compounds, which are used in studies conducted for plant-based therapies to the liver. Other important sources include Phytotherapy Research with 15 publications, Frontiers in Pharmacology, which has published 14 papers, and Phytomedicine, with 11 publications, all of which focus on the pharmacological potential of extracts from natural sources. There are between 9 to 11 articles published in journals such as Nutrients, International Journal of Molecular Sciences, and Food and Chemical Toxicology outlining the biochemical and toxicological properties of plant compounds. International Journal of Nanomedicine (9 articles), Molecules (8 articles), and Pharmaceuticals (8 articles) highlighted the molecular science and nanotechnology aspects of innovative drug delivery systems relevant to natural treatments.

Figure 3 Most relevant sources of research.

We observed an aggregate increase in such articles across time in prominent journals concerning liver health, plant extracts, and drug delivery systems. The most significant trend was in the Journal of Ethnopharmacology, with an increase from 2015 onward, reflecting an upward trend of research in traditional medicinal practices and natural compounds. Phytotherapy Research, Frontiers in Pharmacology, Nutrients, and Phytomedicine also have shown a steady trend, pointing to increased interest in the pharmacological, nutritional, and therapeutic uses of plant-based treatments. A general upward trend for several of these journals highlights an increase in interdisciplinary emphasis on natural therapies and advanced drug delivery for liver health.

Author analysis

We also analyzed author productivity over the years for plant extracts on liver health and drug delivery. The steady production by prominent contributors like Li Y and Wang Q throughout the last decade to better signify how contributions from each of these authors have made a difference over the years.

Figure 4 depicts country production over time for articles in this research area. China had a dramatic increase spurt in output after 2015, followed by other countries, including Egypt, India, Italy, and the United States.

Figure 4 Country production over time.

This trend (Figure 4) clearly signifies the rising interest and contribution from the international community. The surge in articles from China could be due to the strong support of the Chinese government for traditional Chinese medicine. This has led to continuous research achievements in the field of natural products, undoubtedly promoting the research and development and innovation of drug delivery systems in the country.

Figure 5 illustrates a world map of scientific production in this research area by country. Darker shades mean higher research output. The majority of contributions came from China, followed by India, then the United States, along with many European and Asian countries. We analyzed author productivity according to Lotka's Law, which describes the number of authors as a function of their number of publication(s). In this case, most authors have published one or two articles, while a small number have published many more than that, as would be expected according to Lotka's Law in bibliometrics. This suggests that a small fraction of the most productive authors is responsible for most of the research activity in this area.

Figure 5 World map of country scientific production in liver health, plant extracts, and drug delivery.

Figure 6A demonstrates citations of studies on liver health, plant extracts, and drug delivery of the most cited countries. China and the United States have contributed the maximum with 5132 and 4851 citations, respectively. India, Italy, and Iran are the other notable contributors, which depicts their existence in the global scenario. The pattern of citations depicts influence and the acceptance and value of research by these leader countries.

Figure 6 Citation statistics of documents. A: Most cited countries; B: Most globally cited documents.

Chinese institutions have been the leading contributors in terms of number of published articles. Chengdu University of Traditional Chinese Medicine and China Pharmaceutical University are among the most productive Chinese institutions. Other important contributors are Nanjing University of Chinese Medicine and Guangzhou University of Chinese Medicine. This emphasizes the role that universities in China play in the production of research work on liver-targeted natural therapies.

Document and keyword analysis

Figure 6B shows the most global cited documents of any research into the health of the liver, plant extract, or drug delivery. All items on this list are highly influential papers. However, at the top is Asl and Hosseinzadeh[78] in Phytotherapy Research with 1034 citations, while Bagchi (2000)[79] in Toxicology has 977 citations. These papers have triggered profound impacts, often fundamental, and are the most highly referenced topics in the domains of phytochemistry and hepatotoxicity. The contributions of the authors remain immense, not only considering the citations but also the evidence produced in the field.

Figure 7A shows a word cloud of common terms published in this research area. Terms like “plant extract”, “nonhuman”, and “human” are prominent, indicating frequent studies on the effects of plant extracts across different biological models. A few more notable terms include “antioxidant activity”, “liver protection”, and “phytochemical”, highlighting popular research topics related to liver health and bioactive natural compounds.

Figure 7 Word clusters and network analysis. A: Word cloud; B: Network analysis of most frequent themes of studies; C: Network analysis of author collaborations; D: Network analysis of frequently used keywords.

We also studied the frequency of key terms over time in the literature. Some terms, such as "plant extract", "human", and "nonhuman" exponentially increased since about 2010, revealing increasing interest from human and animal studies of plant-based therapies. The steady rise of terms like "antioxidant activity" and "drug bioavailability" underscores growing research into enhanced the efficacy of natural compounds.

Co-occurrence and clustering

Figure 7B is an illustration of a co-occurrence network of keywords in liver health, plant extracts, and drug delivery research This network clusters the keywords so that such words as "plant extract", "nonhuman", and "antioxidant activity" are centrally positioned within the red cluster, indicating the studies conducted on animal and experimental models.

Conversely, the blue cluster centrally positions terms such as "human", "review", and "drug bioavailability", signifying human studies and pharmacokinetics. This network map (Figure 7B) profiles thematic divisions within the field, with one set based on distinctions between experimental and clinical research contexts.

Figure 7C is a Citation Network of the most significant articles associated with research in liver health, plant extract, and drug delivery. Each node refers to a document, and every line demarcates the citation connection among the articles. The network is divided into clusters that each depict one specific thematic focus. Those nodes that stand out, like Bishayee et al[86] and Bharti et al[87], denote highly cited works that anchor their respective clusters. These clusters reveal certain thematic areas of research, including pharmacological studies, antioxidant mechanisms, and drug delivery innovations.

As shown in Figure 7C, this visualization points out the interconnectivity of foundational studies in the development of narrower thematic areas of specialization within the field.

Thematic analysis

Figure 7D depicts a keyword co-occurrence network divided into two major clusters, which implies that the research effort under liver health, plant extracts, and drug delivery is distinct. The red cluster may be on animal studies and experimental terms like "rats", "animal tissue", "metabolism", and "oxidative stress", which may delineate preclinical studies on the damaging and protective effects of plant extracts on the liver. The blue cluster is more on human-related study, such as pharmacokinetics, and bioavailability, with keywords "bioavailability", "human", "antioxidant activity", and "drug efficacy". This separation in Figure 7D presents the area's contrasting focus between experimental animal models and their application in clinics or clinical practices, which indicates the potential wide applicability of these plant-derived compounds in the given research areas.

We observed a thematic evolution of research topics in liver health, plant extracts and drug delivery from 1981 until 2024. A Sankey diagram traced the flow of significant themes across the three periods, 1981-2000, 2001-2020, and 2021-2024. Within the first period, 1981–2000, the themes were dominated by the issues of "liver", "plant extract", and "clinical trial". Within the 2001-2020 period, "human" and "nonhuman" models emerged as significant, which may be an indicator of the balance between clinical and experimental studies. Within the last years (2021-2024), the focus had returned to "nonhuman" and "article" and could therefore indicate a rise in animal studies and in comprehensive review articles.

Social structure and collaboration networks

We explored the co-authorship network of authors on the topic of liver health, plant extracts, and drug delivery. The basic setup of this co-authorship network was such that clusters illustrated as groups of collaborating authors who frequently appear with each other. Large nodes such as those of Wang et al[47], Kuang H, and Li Y represented central figures with larger widespread connectional networks in different clusters, which indicate their important role in providing bridges between research groups. Another distinct cluster revealed dispersed, isolated nodes on some lines of research, like Kunnummakkara AB and Pattanayak SK, representing specialized research collaborations with little intergroup interaction.

Connections between countries are represented as lines that join one country with another, where the strength of the connection is related to the line thickness and darker lines show stronger and more frequent collaborations. China is clearly the largest hub, and it extensively collaborates with countries across Asia, Europe, and North America. The United States, India, and several European countries play a very important role in this global research network. Figure 8 illustrates the large international collaborative effort needed for research in this area and indicates that cross-border collaborations are instrumental in advancing knowledge and innovations linked with liver health and natural therapeutic compounds.

Figure 8 Country collaboration map in liver health, plant extracts, and drug delivery research.

DISCUSSION

The present bibliometric overview presents an important perspective of the research landscape concerning liver health and plant extracts vs advanced drug delivery systems. The interest in research in liver health, plant-based extracts, and advanced drug delivery systems has changed over the last four decades from basic clinical observations and traditional herbal applications to mechanistic studies and pharmacokinetic innovations. Such a development stands for a world trend toward the integration of traditional knowledge with modern therapeutic approaches. Other studies, like Bharti et al[87], showed that plant extracts were effective in treating liver diseases through their antioxidant and anti-inflammatory actions. Some evidence supports the increasing interest in the use of plant-based remedies as supplements or alternatives in the care of liver health due to their antioxidant and anti-inflammatory effects, including in the setting of hepatotoxicity following the treatment of solid and blood cancers[88,89]. Apart from this progress, the field has its own set of limitations for more clinical or human-based research methods due to cost-effectiveness and lesser popularity of plant-based medications in allopathic medicine.

Thematic progression over this area of research is consistent with a heightened interest in bettering the understanding of molecular mechanisms for the therapeutic effects of plant-based therapies on the health of the liver. For instance, such progress in pharmacokinetics as encapsulation in nanoparticles guaranteed a better availability of curcumin, a compound traditionally known to have poor gastrointestinal absorption. This shift from empirical observations to mechanistic exploration has increased the scientific knowledge of how plant-based compounds act on liver physiology and has thus made these therapies more feasible for introduction into clinical practice. This development attests to how natural products can be tolerated by stringent standards in modern medicine, where the scientific goal is the optimization of therapeutic efficacy with traditional compounds[90].

Advanced drug delivery systems have revolutionized the therapeutic landscape for treatments using plant derivatives for liver diseases. One of the more traditional compounds, silymarin, is limited in its effectiveness due to poor solubility and absorption. Kuppusamy et al[91] demonstrated that, silymarin encapsulated with nanoparticles significantly increases the protective effects towards liver tissue and anti-inflammatory actions as compared to the free form. Recently, Isbrucker et al[92] showed that curcumin formulations in liposomes enhanced its bioavailability and efficacy by taking full advantage of encapsulation technologies. This is an essential step forward, as bioavailability and stability have been major limitations in the therapeutic use of natural products and plant extracts.

International collaborations identified high numbers of researchers from China, the United States, and India among others. This is an indication that researchers around the world share a common concern and interest in verifying age-old medicinal practices using modern research methods. Liu et al[93] affirmed that collaborations between Chinese and Western researchers have helped develop innovative applications for traditional Chinese medicine in treating liver disease. The leading position of China in this sector is very much attributed to its support for research on traditional medicine, which Chinese institutions have used to their advantage to produce remarkable contributions. For example, Liu et al[93] found that government support and investment in traditional medicine catapulted China to more solid positions in the research of liver health, emphasizing the power of cross-border collaborations in advancing the potential therapeutic application of natural compounds.

Despite these promising potentials of plant-based therapies for liver health, several challenges and limitations exist. The main drawback was related to variability in the composition of plant extracts due to factors such as geographic origin and extraction methods. Variability makes standardization challenging, thereby imparting a lack of credibility to therapies relating to therapeutic outcomes. This inconsistency complicates the assessment of efficacy and dosage in a clinical setting. Toward this end, Lee et al[94] suggest using bioinformatics and molecular docking studies for scientists to identify specific bioactive compounds that may be interacting with receptors in liver cell lines. This approach can help optimize the therapeutic use of plant extracts.

Furthermore, most of the existing research studies on plant-based liver therapies are conducted on animal models, so the results cannot be directly extrapolated into human applications. The mechanistic understanding of such animal studies are valuable, but physiological differences when translating such data into clinical practice introduce difficulties. Human clinical trials should be conducted to confirm the efficacy seen in preclinical studies[95]. Future human studies need to be designed more robustly to ascertain the therapeutic efficacy of these compounds and their safety profiles in patients with liver diseases.

The escalating worldwide trends in liver diseases, such as NAFLD and fibrosis call for effective and accessible treatments. Plant-based therapies represent a promising development in complementary therapies in the possible additional mechanisms used concomitantly with conventional treatment approaches. Studies like those of Parama et al[96] and Surai[97] have shown the beneficial effects of compounds such as curcumin, silymarin, and berberine, including anti-inflammatory, antioxidant, and lipid-modulating activities that are foreseen to efficiently support liver function and slow disease progression. Thus, phytochemicals could prove helpful adjuncts for treating liver diseases, potentially working through a multi-targeted approach well adapted to the complex pathophysiology of chronic liver disorders.

Similarly, quercetin and naringenin are two flavonoids that have been proven by Du et al[98] to show anti-fibrotic properties, which are highly beneficial in treating liver fibrosis. The results conclude that the development of these plant-based compounds has a bright future in preventing liver damage and reversing pathological changes of chronic liver conditions. Therefore, the utilization of herbal-based therapies is increasingly becoming a promising choice for patients as supplements to conventional pharmaceutical drugs.

Concerning plant-based therapies on the aspect of liver health, there are encouraging findings based on existing literature. However, many studies have some reservations in terms of sample sizes and study designs. The methodologies adopted for research may vary considerably and have non-standardized protocols, which largely contribute to the inconsistencies between the studies. This makes it challenging to draw certain conclusions into clinical practice recommendations. Further, the long-term safety of these substances remains largely uninvestigated in patients with compromised liver functionality.

CONCLUSION

This bibliometric study reveals that the interest in a plant-based therapy for an optimal level of liver health is growing and continues to as advanced drug delivery technologies are developed. Large-scale and human-randomized further studies are recommended to validate the therapeutic value of these compounds. Standardization of extraction and formulation procedures is needed to ensure the results in different studies can be consistent. A multidisciplinary approach including pharmacology, molecular biology, and clinical trials is necessary to fully enable the therapeutic advantage of plant-based compounds. The therapies are destined to become integrated into standard treatment processes, hence reaching effective, accessible, and safe approaches to managing chronic disorders of the liver through further research and international cooperation.