Global research trends in liver regeneration and immunomodulation: A perspective from bibliometric analysis

ABSTRACT

Liver regeneration is a complex process involving multiple cells, in which immunomodulation plays an important role in the process. However, there is lack of a comprehensive and objective summary of the current state of research and trends in the field. We retrieved articles on liver regeneration and immunomodulation published from 2004/01/01 to 2024/09/26, from the Web of Science Core Collection database. Authors, institutions, countries, journals and references were analyzed using bibliometric methods via CiteSpace and VOSviewer. A total of 4,992 articles were searched involving 102 countries or regions, 4,027 institutions and 26,830 authors. China is the country with the most articles in this field, and the United States ranks first in terms of citation/publication ratio (56.41). c-Met, liver regeneration, mesenchymal stem cells, extracellular matrix and angiogenesis are current research hotspots. While liver regeneration, targeted therapy, acute liver failure, hepatocellular carcinoma and mesenchymal stem cells are the themes and trends in this field. The study summarizes the research results in the field of immunomodulation and liver regeneration, and comprehensively analyses the research hotspots and trends, and provides an important basis for future applications and advances in the field.

Introduction

Hepatocellular carcinoma, the fourth leading cause of cancer-related deaths, has various treatment options, including liver transplantation, partial hepatectomy, percutaneous ablation, radiotherapy and interventional embolization.^1,2 Liver transplantation is the most effective life-saving option for patients with acute hepatic failure, giant hepatocellular carcinoma or end-stage cirrhosis.^3,4 However, partial hepatectomy remains the cornerstone of curative treatment for patients with early cirrhosis or localized hepatocellular carcinomas with preserved liver function.⁵ The liver, as the only solid organ with high regenerative capacity and a central immune regulatory organ, can rapidly restore its size and function through the proliferation and immune regulation of its own cells when faced with endogenous or exogenous injury.^6,7 Innate and adaptive immunity are involved in the regulation of liver regeneration. Innate immunity, such as Kupffer cells and natural killer cells, recognizes and removes damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), reduces hepatocellular damage, and releases TNF-α and IL-6 to promote liver regeneration.⁸ Whereas adaptive immunity, such as CD8⁺ T cells secrete IFN-γ to regulate liver regeneration, regulatory T cells (Tregs) secrete IL-10 and TGF-β to inhibit excessive immune responses, prevent hepatocyte damage, and promote liver regeneration.⁹

Immunomodulation is a dynamic and complex process that balances various mechanisms within the body to protect the host, tissues, and cells.¹⁰ Immunomodulation has rapidly evolved into a powerful therapeutic tool to regulate the immune system for treating diseases through various modalities.¹¹ Common immunomodulatory therapies include immune checkpoint inhibitors, cancer vaccines, Tregs and immunoediting.^12–14 These therapies are now widely used to treat various diseases, including hepatocellular carcinoma, gastric carcinoma, lung cancer, breast cancer and glioma, and have achieved encouraging long-term outcomes.^15–19 During liver regeneration, the interplay of multiple immune cells orchestrates hepatocyte proliferation and growth. Kupffer cells kick-start liver regeneration by secreting cytokines like IL-6 and IL-1β. Macrophages aid this process by releasing TGF-β, and mesenchymal stem cells (MSCs) enhance liver regeneration by upregulating autophagy-associated protein (LC3) and reducing Kupffer cell infiltration.^20,21 Nevertheless, liver regeneration is intertwined with immune tolerance. Tregs in the liver preserve immune tolerance by inhibiting immune cell activation through cytokines such as IL-10 and TGF-β. Additionally, biliary epithelial cells, with their low major histocompatibility complex (MHC) expression, struggle to activate T cells, thereby fostering immune tolerance.^22,23 Collectively, these immune modulations cultivate a conducive environment for liver regeneration, mitigate rejection and drive the liver toward regeneration and functional restoration. To visualize future trends in liver regeneration and immunomodulation, a comprehensive analysis of the current state of research is essential.

In 1955, Eugene Garfield introduced the term “citation classic” for the most cited scientific articles in the Institute for Scientific Information (now known as Web of Science) database.²⁴ Since then, bibliometrics has gradually evolved, culminating in Pritchard’s introduction of the term in 1969.²⁵ The JAMA Network is currently the leading platform for publishing bibliometric articles.^26,27 Bibliometric analyses, which typically encompass bibliometrics, data processing and data analysis were performed using two tools: CiteSpace and VOSviewer, have been employed to explore the productivity of researchers, institutions and countries within specific fields, aided researchers in understanding the dynamics and trends of research.^28–30 It is widely used in the study of various diseases, such as periodontal disease, hypertension, autoimmune diseases and in various systems, including the immune, digestive and nervous.^29,31,32 However, no bibliometric studies on liver regeneration and immunomodulation have been reported. Therefore, the aim of this study was to visualize and analyze research on immunomodulation in the liver regeneration, to understand the current status, hotspots and future trends in this field.

Methods and materials

Data and research program

The Web of Science Core Collection (WoS) database offers superior accuracy in annotating literature types compared to other databases and is considered the optimal choice for literature analysis; therefore, we selected this database for our search.³⁰ We searched the WoS database for articles related to immunomodulation and liver regeneration research published from 2004/01/01 to 2024/09/26, using the following search formula: (((((((TS=(“hepatocyte regeneration”)) OR TS=(“hepatocyte growth”)) OR TS=(“liver cell regeneration”)) OR TS=(“regeneration of hepatic cells”)) OR TS=(“liver regeneration”)) OR TS=(“hepatic regeneration”)) OR TS=(“hepatocyte proliferation”)) OR TS=(“hepatocellular regeneration”)) AND TS=(“immune”) OR TS=(“Immune Checkpoint Inhibitor”). The retrieval format is shown in Figure 1. Literature screening for this study was based on the following inclusion criteria: (1) full-text articles containing information about immunomodulation and liver regeneration; and (2) articles and review manuscripts published in English. The exclusion criteria were as follows: (1) topics unrelated to immunomodulation and liver regeneration; (2) articles that were conference abstracts, news items or briefs. Plain text versions of the selected articles were exported. Two researchers independently reviewed the articles by reading the abstracts. If a disagreement arose, a third researcher was brought in to make a determination. The results were then summarized and consolidated for subsequent analysis.

Figure 1.

Flowchart of literature search on liver regeneration and immunomodulation.

Data analysis

GraphPad Prism v8.0.2 analyzes and visualizes annual publication counts, global trends and rates.³³ Additionally, CiteSpace (6.2.4 R (64-bit)) and VOSviewer (v. 1.6.18) were employed to analyze the data and visualize the scientific knowledge graph.^34,35

VOSviewer v1.6.18, developed by Waltman et al. in 2009, is free JAVA-based software designed for analyzing large volumes of literature data and displaying it in a mapped format.³⁶ To visualize research results in a specific field by mapping the literature co-citation network, CiteSpace (6.2.4 R) software, developed by Chao-Mei Chen, was employed. This software examines new concepts and evaluates existing technologies within an experimental framework.^37,38 This approach enables researchers to gain a better understanding of knowledge domains, research frontiers and trends, thereby predicting future research.

Results

The results indicate that the WoS database contains 4,992 articles related to immunomodulation and liver regeneration. Since 2004, the annual publication count has gradually increased, peaking in 2014 (Figure 2). This trend shows that the field has received increasing attention over the past two decades, providing a rich literature base for further in-depth research.

Figure 2.

Annual number of articles published in liver regeneration and immunomodulation. The black curve is the fitted trend line.

Analysis of national published articles

Research on the application of immunomodulation and liver regeneration has been conducted in 102 countries or regions. Figures 3a, b show the top 10 countries in terms of the number of articles published over the past and present their annual publication trends. Supplementary Table S1 indicates the top 10 countries in publication count. The collaboration network depicted in Figure 3c reveals extensive collaborative efforts among various countries or regions. The United States collaborates closely with countries such as the United Kingdom, Italy and Germany, while China collaborates closely with Japan, Korea and the Netherlands. This international cooperation network not only promotes the exchange of knowledge and technology, but also accelerates research progress in this field, driving joint progress among countries in the areas of immunomodulation and liver regeneration.

Figure 3.

(a) Line graph of national publications. (b) Heat map of national publications. (c) Networks of country cooperation. The more articles published, the larger the nodes shown in the graph. Purple circles represent centrality greater than 0.1.

Analysis of institutions and their cooperation

The study of immunomodulation and liver regeneration is attracting mounting worldwide attention. A total of 4,027 institutions published articles related to the field. Table 1 presents the top 10 institutions by publication count. Figure 4 illustrates the strength of collaboration between institutions. These institutions play a key role in promoting research and development, and cooperation between institutions helps to integrate resources and provide stronger scientific research capabilities to tackle difficult problems in this field.

Table 1.

Top 10 institutional published literature.

Rank	Institution	Country	Number of studies	Total citations	Average citation
1	University of California System	USA	127	7881	62.06
2	Harvard University	USA	107	8098	75.68
3	Institut National de la Sante et de la Recherche Medicale (Inserm)	France	96	4333	45.14
4	Pennsylvania Commonwealth System of Higher Education (PCSHE)	USA	96	6478	67.48
5	National Institutes of Health (NIH) – USA	USA	87	4912	56.46
6	University of Pittsburgh	USA	85	5874	69.11
7	University of Texas System	USA	80	4849	60.61
8	Zhejiang University	China	79	2066	26.15
9	Shanghai Jiao Tong University	China	69	2548	36.93
10	Harvard Medical School	USA	69	6100	88.41

Figure 4.

Networks of institutional co-operation on liver regeneration and immunomodulation. Node size represents the number of publications, while link size indicates the strength of the collaboration. The color shifts from purple to yellow between 2004 and 2024.

Analysis of article output and impact of journal

Analyzing journal publication and citation patterns is crucial for understanding the research landscape. Supplementary Table S2 lists the top 10 journals with the highest number of articles and most cited articles in liver regeneration and immunomodulation, along with cross-citations. Figure 5a depicts a density map of journals based on their published articles. Supplementary Table S3 indicates the co-cited journals. Figure 5b displays a network map showing co-citations between journals. Figure 6 shows the thematic distribution of journals and cross-citations through a double map overlay. Research published in journals in the fields of molecular/biology/genetics and health/nursing/medicine is primarily cited by studies published in journals focusing on molecular/biology/immunology and medicine/medical/clinical research, respectively. These journals serve as important platforms for disseminating research findings. Their publication and citation patterns reflect the research hotspots and development trends in the field, providing a reference for researchers to select appropriate publication channels and a basis for in-depth analysis of research dynamics and influencing factors.

Figure 5.

(a) Density map of journal publications. Font size and circle size are associated with higher co-occurrence frequency, and the color from green to red represents positive correlation with frequency. (b) Co-citation network map of journals. Different nodes represent different journals, with larger nodes represents more publications. The color shifts from purple to yellow between 2004 and 2024.

Figure 6.

Dual map of journals on liver regeneration and immunomodulation. Colored tracks represent citation links, with citing journals on the left and cited journals on the right, revealing two primary citation paths.

Analysis of published and co-cited authors

Identifying leading authors in liver regeneration and immunomodulation research is vital for grasping key research contributors and their impacts. Table 2 lists the top 10 authors with the highest number of articles and citations. Figure 7 presents the network visualization analysis of author collaboration and cross-citation using CiteSpace. These authors and their collaborative networks play a leading role in advancing research in this field. Their research findings and academic perspectives often carry significant authority and influence, providing important references and insights for other researchers.

Table 2.

Top 10 author’s articles and co-citation on liver regeneration and immunomodulation.

Rank	Author	Count	Rank	Co-cited author	Citation
1	Nakamura, Toshikazu	29	1	Michalopoulos G.K	602
2	Matsumoto, Kunio	25	2	Nakamura T	540
3	Wang, Hua	22	3	Fausto N	495
4	Fujishita, Akira	19	4	Matsumoto K	363
5	Wang, Wei	19	5	Birchmeier C	297
6	Xu, Cunshuan	17	6	Higgins G.M	255
7	Gao, Bin	16	7	Taub R	209
8	Kataoka, Hiroaki	16	8	Bottaro D.P	182
9	Kitajima, Michio	15	9	Wang Y	177
10	Masuzaki, Hideaki	15	10	Trusolino L	171

Figure 7.

(a) Cooperation network of authors. Node size represents the number of publications, while link size indicates the strength of the collaboration. (b) Co-citation network of authors. Node size increases as the number of co-citations rises. The color shifts from black to yellow between 2004 and 2024.

Analysis of co-cited references in published articles

The top 10 articles with the highest number of citations in the field of liver regeneration and immunomodulation are shown in Supplementary Table S4, while Supplementary Figure S1 shows that the co-citation reference network has 1,406 nodes and 5,597 links. To uncover research hotspots and trends in the field, we conducted co-citation and temporal cluster analyses on articles published over the past years (Figure 8a, b). We found oval cell (cluster3), c-Met (cluster4), transdifferentiation (cluster10), endometriosis (cluster11), materiptase (cluster12), islets (cluster17), oral squamous cell carcinoma (cluster18) and cca (cluster19) were the hot spots of early research. Met (cluster0), hepatocyte growth factor (cluster1), hepatocyte differentiation (cluster6), myocardial infarction (cluster13), immunomodulation (cluster14), partial hepactomy (cluster15), matrix metallopeptidases (cluster16) and cd34 fibroblasts (cluster20) are mid-term research hotspots. Liver regeneration (cluster2), targeted therapy (cluster5), acute liver failure (cluster7), hepatocellular carcinoma (cluster8) and mesenchymal stem cell (cluster9) are the current research hotspots in this field. The evolution of these research hotspots reflects the shift in focus and the continuous deepening of research in this field, providing a basis for determining future research directions and the rational allocation of research resources.

Figure 8.

(a) Peak map of co-cited literature, shows the changing trends in different co-cited literature clustering from 2004 to 2024. (b) Clustering of co-cited literature, with different colors representing clusters.

Analysis of keywords for high-frequency searches

Analyzing keywords offers a quick way to grasp the current state and future direction of the research field. The most popular keyword was hepatocyte growth-factor (1,392), followed by c-Met (589), activation (486), proliferation (407) and receptor (361) (Table 3, Figure 9a, b). We constructed a network containing 165 keywords with at least 41 occurrences, yielding a total of 4 different clusters. Cluster 1 (red) had 55 keywords including hepatocyte growth factor, inhibitor, c-Met, beta catenin, breast cancer, resistance, egfr, receptor, progression, mutation, amplification, signaling pathway, association, biomarker, down regulator, immunotherapy, migration, protein. Group 2 (green) has 53 keywords including activation, apoptosis, proliferation, resection, hepatectomy, injury, inflammation, t cell, infection, dendritic cell, cytokine, immune response, innate immunity, interleukin-6, macrophage, mechanism, messenger rna, nf kappa b, regulator t cell. Group 3 contains 41 keywords (in blue), including acute liver failure, adipose tissue, cell therapy, delivery, differentiation, extracellular matrix, fibrosis, gene therapy, growth factor, model, repair, marrow stromal cell, immunomodulation, liver fibrosis, progenitor cell, stem cell. Group 4 contains 16 keywords (in yellow) including angiogenesis, biomarker, chemokine, collagen, cytokine, endothelial growth factor, fibroblast, serum, vegf. We plotted a volcano map via CiteSpace to visualize the research hotspots over time (Figure 9c, d). High-frequency keywords and their clusters reflect the core research themes and popular research directions in this field, providing strong support for researchers to grasp the cutting edge of research and determine research priorities.

Table 3.

Top 10 high frequency keyword on liver regeneration and immunomodulation.

Rank	Keyword	Counts	Rank	Keyword	Counts
1	Hepatocyte Growth-Factor	1392	11	Apoptosis	293
2	C-Met	589	12	Injury	260
3	Activation	486	13	Fibrosis	252
4	Proliferation	407	14	Partial-Hepatectomy	245
5	Receptor	361	15	Therapy	232
6	Differentiation	353	16	Hepatocytes	224
7	Transplantation	338	17	Stromal Cells	219
8	Inflammation	337	18	Bone-Marrow	204
9	Angiogenesis	324	19	Hepatocellular-Carcinoma	204
10	Stem-Cells	310	20	Progenitor Cells	194

Figure 9.

(a) Density map of keywords. Font size and circle size are associated with higher co-occurrence frequency, and the color from green to red represents a positive correlation with frequency. (b) Network map of high-frequency keywords, the size of the node represents frequency. (c) Peak map of keyword clustering, shows the changing trends in different keyword clusters from 2004 to 2024. (d) Clustering map of keywords, with different colors representing clusters.

Reference and keyword analysis of co-citation outbursts

Citation outbursts often highlight emerging research hotspots or trends. Figure 10a shows the 50 most reliable citation literature in the field of immunomodulation and liver regeneration. Figure 10b illustrates the 50 keywords with the strongest citation outbursts in the field. These bursts in citations for keywords and references signify current research hotspots and indicate potential research directions. These frequently cited keywords and references reveal current research hotspots and suggest potential research directions, helping researchers keep abreast of the latest developments in the field and providing inspiration for innovative research.

Figure 10.

(a) Bursting map of cited literature; (b) Bursting map of keywords. The red bars show both duration and intensity of the burst, signifying the keyword’s importance in the field.

Discussion

A bibliometric analysis of literature on liver regeneration and immunomodulation from 2004/01/01 to 2024/09/26, identified 4,992 articles published across 102 countries or regions, involving 4,027 institutions and 26,830 authors. The field saw its lowest output in 2004, with 177 articles, followed by steady growth that culminated in a peak of 302 articles in 2014. Since then, the number of articles has slightly declined, this may be attributed to global advances in hepatitis virus treatment and the rollout of prevention strategies (such as infant prophylaxis and early vaccination) have contributed to a slowdown in the progression of liver disease and a reduction in the number of liver surgeries, including liver transplantation and partial hepatectomy.³⁹ The annual average of over 200 articles reflects a consistent and sustained interest, indicating that the field remains both active and productive, this may be related to the fact that approximately 250 million people worldwide are infected with hepatitis B virus (HBV), that HBV and hepatitis C virus (HCV) remain the leading causes of hepatocellular carcinoma and overall mortality globally.⁴⁰ The underlying reasons for this sustained growth extend beyond the liver’s unique role as the only parenchymal organ capable of regeneration. The rapid advancement of liver transplantation, partial hepatectomy and liver regeneration therapies, particularly for the treatment of hepatocellular carcinoma, liver failure and liver injury, has brought the field into clinical focus. Simultaneously, breakthroughs in immunomodulation and molecular biotechnology have propelled research by introducing new therapeutic tools and methods.^41–45

In the field of liver regeneration and immunomodulation, the top 5 countries in terms of the number of articles are China, the United States, Japan, Germany and Italy. China ranked first in terms of the number of articles (1,340), accounting for 26.84% of the total number of articles, and ranked second in terms of the number of citations (31,555). This indicates that China has invested a lot of research in the field. At the same time, China as a developing country, has made an important contribution in the field of liver regeneration and immunomodulation research. The United States ranked second with 26.06% of total articles 73,394 citations, and ranked first with a citation/publication ratio (56.41), with a centrality of 0.59. This confirms that the United States has made a critical contribution and is in the leading position in terms of the citation/publication ratio, which may be related to the strong economic strength, policy support and high medical investment levels.

Among the top 10 ranked institutions publishing articles in liver regeneration and immunomodulation, American institutions accounting for 70% of the total. This may be related to the leading position of the United States in this field, with its high-impact English-language journals, substantial research funding and extensive international scientific collaborations. The University of California ranked first in the number of articles published, contributing 127 articles with 7,881 citations, averaging 62.06 citations per articles. An analysis of the institutional collaboration network reveals that institutions tend to collaborate primarily with others within their own country, which may increase the chances of cross-citation of articles from their own countries.⁴⁶ To further advance research in this field globally, we advocate for domestic and international institutions to build more collaborative relationships. Enhanced cross-border cooperation, leveraging diverse expertise and resources, will accelerate scientific advancement.

Journals are essential in academia and specialized fields, serving as key channels for researchers to disseminate their work. Top journals, in particular, play a critical role in publishing significant research.^47–49 About the field, PLOS ONE leads with 112 articles, followed by Hepatology with 103 articles. The Journal of Hepatology holds the highest impact factor among the top 10 journals. A journal’s impact is measured by how frequently it is co-cited, reflecting its influence on the scientific community to some extent.^25,50 PNAS has the highest number of co-citations (2,651), followed by Journal of Biological Chemistry (2,242) and Nature is cited 2,100 times. Among the top 10 journals in terms of articles and co-citations, 90% are ranked in Q1 and Q2, indicating that the research in this field is generally of high quality. This also highlights the need for more in-depth studies in this area moving forward.

An influential contributor to the field of liver regeneration and immunomodulation is Nakamura T from Japan, with 29 articles in the past years, followed by Matsumoto K with 25 articles. However, Michalopoulos G.K. holds greater academic influence, with his articles receiving 602 citations during this period, ranking first among the top 10 authors in both co-citations and total citations. This prominence is closely tied to his article “Liver Regeneration: Biological and Pathological Mechanisms and Implications” published on Nature Reviews Gastroenterology & Hepatology, which has been cited 495 times. In a recent report, Michalopoulos G.K. identified mechanoregulatory signaling, EGFR and MET, and the YAP signaling pathway as regulators of liver regeneration, controlling the induction and maintenance of liver size and weight (“heparin regulators”) before regeneration begins.^51,52

Keyword analysis in this field provides valuable insight into current research trends. We further used CiteSpace to cluster keywords over time, which allowed us to visualize evolving research hotspots. Our analysis revealed that c-Met, liver regeneration, MSCs and angiogenesis are the current key topics of interest. This may be related to the fact that “Liver Regeneration: Biological and Pathological Mechanisms and Implications” is currently experiencing a citation burst in the field. Research has shown that c-Met promotes liver regeneration by activating extracellular signal-regulated kinase (ERK) and facilitating nuclear translocation. It also serves as a critical receptor for hepatocyte growth factor, regulating pathways such as JAK/STAT3, PI3K/Akt/NF-κB, which are essential for hepatocyte generation and proliferation.^53,54 In contrast, MSCs contribute to liver regeneration through several mechanisms: they migrate to the liver, participate in immunomodulation, differentiate into hepatocytes and engage in paracrine signaling. Additionally, MSCs release lipids, free nucleic acids and soluble proteins that aid liver regeneration.^55,56 During partial hepatectomy or acute liver injury, hepatic sinusoidal endothelial cells promote angiogenesis and liver regeneration by sensing shear stress changes and interacting with platelets and inflammatory cells.⁵⁷ Simultaneously, hepatic stellate cells activate the expression of pro-angiogenic factors under hypoxic conditions, accelerating vascularization and liver regeneration.^58–60

To identify research hotspots and trends in liver regeneration and immunomodulation, we conducted a time-based cluster analysis of co-cited literature in this field over the past years. Our analysis reveals a progressive focus shift in research topics. Early research centered on oval cells, c-Met and transdifferentiation. The extensive investigation into oval cells, which can rapidly differentiate into hepatocytes after hepatectomy, reflects the foundational role of understanding cell differentiation mechanisms in liver regeneration. The exploration of factors like Th1, IFN-γ, and connective tissue growth factor (CTGF) that promote oval cell expansion further underscores the importance of identifying key players in cellular processes.^61–63 What’s more, the intricate regulatory mechanisms involving immune mediators such as TNF-α and IL-6, which upregulate Zip14 to enhance c-Met phosphorylation, and lncHand2-triggered Nkx1–2 expression that activates c-Met, highlight the complex interplay of signaling pathways and molecular interactions in driving liver regeneration.^64,65 Mid-stage research delved into the Met and hepatocyte growth factor. The HGF/c-Met axis, as one of the two most important signal transduction pathways in liver regeneration, has garnered significant attention due to its critical role in stem cell-mediated liver regeneration.^66,67 Hepatocyte growth factor binds to the Met receptor on the surface of hepatocytes, activating the tyrosine kinase activity of the Met receptor, which in turn activates multiple signaling pathways, such as MAPK/ERK, PI3K/Akt and STAT3. These signaling pathways work together to promote the progression of hepatocytes from the G1 phase to the S phase, facilitating hepatocyte proliferation, while inhibiting hepatocyte apoptosis, thereby providing the cellular basis for liver regeneration.⁵¹ Additionally, the elimination of MET and EGFR signaling pathways inhibits hepatocyte proliferation, impairs liver recovery after partial hepatectomy, and leads to liver decompensation.⁶⁸ These findings collectively emphasize the need for a comprehensive understanding of the molecular underpinnings of liver regeneration. Current research has shifted toward more clinically oriented topics like liver regeneration itself, targeted therapy and MSCs. Targeted therapy has emerged as a major focus due to its potential for precise regulation of key targets, offering a promising approach to enhance treatment efficacy and reduce adverse reactions. This shift toward targeted therapy reflects the ongoing efforts to translate basic research findings into effective clinical treatments. Meanwhile, the growing interest in MSCs is driven by their remarkable immunomodulatory, multidifferentiation, and tissue repair capabilities, as well as their relative accessibility. This focus on MSCs signifies the recognition of cell-based therapies as a crucial avenue for advancing liver regeneration research and addressing clinical challenges in liver diseases.⁵⁶

MSCs are widely derived from organs such as the heart, liver and lungs, are easy to culture and expand, have low immunogenicity and immunomodulatory properties, and promote liver regeneration and alleviate liver damage. MSCs not only stimulate liver regeneration by reducing fat accumulation and promoting paracrine mechanisms, but also improve mitochondrial damage by enhancing liver glycogen production, activating the GSK-3β/β-catenin and mTOR pathway, promote β-oxidation and liver regeneration.⁶⁹ Additionally, extracellular vesicles and microvesicles derived from MSCs also promote liver regeneration.⁷⁰ Bone marrow-derived MSCs (BM-MSCs) transplantation can suppress liver stress responses and enhance liver regeneration therapy for APAP induced liver injury.⁷¹ Treatment with BM-MSCs in patients with ursodeoxycholic acid-resistant primary biliary cirrhosis (PBC) and alcohol-related liver fibrosis demonstrated that BM-MSCs promote liver regeneration and repair, improve patients’ quality of life without transplant-related adverse reactions.^72,73 MSCs also exhibit anti-apoptotic effects and promote liver regeneration. Co-culturing hepatocytes with MSCs derived from umbilical cord or adipose tissue increased hepatocyte survival rates, suggesting that hepatocyte and MSCs transplantation may be a promising strategy for treating acute liver failure (ACLF).⁷⁴ Shi et al. found that umbilical cord mesenchymal stem cells (UC-MSC) secrete high levels of liver growth factors, promoting hepatocyte proliferation, as evidenced by increased levels of the liver synthesis marker ALB and decreased levels of the liver injury marker TBIL, thereby improving the survival rate of ACLF patients.⁷⁵ The CD44 on the surface of MSCs binds to E-selectin on endothelial cells, regulating endothelial cell migration and promote liver regeneration.⁷⁶ Additionally, the paracrine function of MSCs promotes angiogenesis by regulating endothelial cell proliferation, migration and angiogenesis, enhancing the release of growth factors in damaged tissues to promote liver regeneration.⁷⁷ In summary, MSCs are crucial for promoting liver regeneration and repairing liver, and further research is needed to elucidate the mechanisms by which MSCs-immune cell interactions promote liver regeneration.⁷⁸

Other immunotherapies, such as immune checkpoint inhibitors, cytokines and immunomodulators, also play a significant role in liver regeneration research. Immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4) suppress T cell activity and inhibit immune responses, thereby allowing tumor cells to escape. Immune checkpoint inhibitors can release the suppression of immune checkpoint molecules on T cells, restoring the antitumor function of effector T cells, are widely used in patients with hepatocellular carcinoma.⁷⁹ For patients with hepatocellular carcinoma, combined treatment with immune checkpoint inhibitors followed by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) not only promotes the regeneration of residual liver tissue but also provides an opportunity for complete tumor resection in patients with hepatocellular carcinoma.⁸⁰ However, some studies have shown that immunotherapy-induced excessive activation of immune cells leading to inflammation and cytokine release may cause liver damage.⁸¹ Therefore, further scientific research is needed to elucidate the specific regulatory mechanisms of immunotherapy on the liver regeneration process.

CiteSpace conducted a citation burst analysis of keywords and references. We found that among the top 50 references cited before the citation burst, 41 were published between 2004 and 2024, indicating that these articles were frequently cited over the past 20 years. Seven of these articles were in citation peak, suggesting that research on liver regeneration and immunomodulation will continue to attract attention in the future. We found that “regulatory T cells” is the current citation burst keyword in the field, suggesting that regulatory T cells (Tregs) may be the research trend in this field. Tregs are a subset of immune T cells that regulate tissue repair and regeneration through their ability to suppress immune responses and maintain immune homeostasis.⁸² Wang et al. found that Tregs secrete IL-10 to induce macrophages to polarize from M1 to M2, reduce macrophage secretion of IL-6 and TNF-α, maintain the inflammatory environment in the liver, and promote liver regeneration.²³ The liver can regulate the IL-33/ST2 axis by establishing Tregs lymphocyte, release amphiregulin to promote liver tissue repair and regeneration.^83–85 In the liver, Tregs increase in expression and inhibit liver fibrosis after carbon tetrachloride (CCl₄) stimulation, while Tregs depletion releases tissue immune responses, exacerbating acute liver injury. Tregs cell depletion combined with CCl₄ stimulation leads to an increased Th2/Th1 cell ratio and increased infiltration of Ly6C⁺ CCR2⁺ myeloid cells, exacerbating liver injury.⁸⁴ Tregs secrete immunosuppressive cytokines (TGF-β, IL-35) to alleviate liver fibrosis, suppress inflammatory responses and excessive immune reactions, and promote liver regeneration.^86–88 Tregs can also secrete CD39 and CD73, promoting the conversion of extracellular ATP into adenosine, which binds to effector T cells, reducing the damage caused by effector T cells to liver cells and promoting liver regeneration.⁸⁹ Additionally, NKT cells promote the expression of IL-12, leading to increased IFN-γ, ultimately inhibiting liver regeneration after partial hepatectomy. NKT cells can also promote liver regeneration after liver transplantation by secreting cytokines in the liver microenvironment to assist in macrophage phenotype reprogramming.^90,91 M2 Kupffer cells (KCs) can both directly inhibit the activation of NK cells through direct cell contact and indirectly regulate cytokine-mediated inhibition, thereby promoting liver regeneration.⁹²

Through visual analysis of the field of liver regeneration and immunomodulation using CiteSpace and VOSviewer, we have gained further insight into the hotspots and trends in this field. As an innate immune organ, liver contains a large number of immune cells, such as Kupffer cells, macrophages, T lymphocytes and NKT cells. immunomodulation plays a crucial role in liver repair and regeneration. The liver regeneration process is regulated by multiple signaling pathways, including Hedgehog, WNT, β-catenin, and various cytokines such as TGF-β, hepatocyte growth factor, IL-6 and TNF-α. These signals are rapidly activated after liver injury and induce hepatocyte proliferation.^7,51 The mutual transformation between hepatocytes and cholangiocytes may be an important direction for future research on liver regeneration, However, it is important to be cautious that chronic loss of hepatocytes may lead to chronic liver diseases such as liver fibrosis, cirrhosis and hepatocellular carcinoma.^93,94 At the same time, liver regeneration is a process involving multiple molecules and pathways, including initiation, proliferation and termination.⁹⁵ The initiation stage mainly involves lipopolysaccharides, Toll-like receptors, TNF-α, IL-6, and other immune-related cytokines.^96–98 During the proliferation phase, it is primarily associated with signaling pathways such as IL-6/JAK/STAT-3 and PI3K/PDK1/AKT.^95,99,100 In the termination phase, it primarily involves molecules such as TGF-β, integrin-linked kinase (ILK) and caspase-3.^101–103 In summary, liver regeneration is the result of a balanced regulation between pro-growth and anti-growth factors, with immunomodulation playing a crucial role in this process. Further research into immunomodulation in liver regeneration may become a future research focus, and its findings could provide significant value for clinical treatments such as partial hepatectomy or liver transplantation in patients with acute liver failure, hepatocellular carcinoma or liver injury.

Limitations

Firstly, this study only collects literature that includes the WoS database, which mainly includes journals from North America, Western Europe and a few developed regions, while some excellent local journals from Latin America, Eastern Europe, the Middle East and parts of Asia fail to be included in Web of Science, resulting in the omission of excellent literature from other databases. Second, the analyses were limited to English-language articles, which resulted in the exclusion of high-quality research from non-native English-speaking regions (Latin America, the Middle East and Asia). Additionally, conference abstracts and proceedings relevant to the field were not incorporated into the study, which may have resulted in the omission of significant research findings. The study only analyzed articles published between 2004/01/01 and 2024/09/26, and recent high-quality articles may have a citation lag, which needs to be tracked and updated in future studies. Finally, self-citations may exaggerate the influence of certain authors, and excessive self-citations may create the illusion that authors are more closely related to research than they actually are when it comes to co-citation analyses, while ignoring the contributions of other scholars. Journal level bias, on the other hand, solidifies the status of high-impact journals through the citation screening mechanism, making the keyword analysis overly focused on mainstream research directions and ignoring some potential hotspots of innovation. Despite these limitations, this study provides valuable insights into research trends, hotspots, and directions in the field of liver regeneration and immunomodulation.

Conclusion

Immunomodulation remains a major focus in the study of liver regeneration, with Tregs emerging as a key research trend. Understanding the mechanisms of immunomodulation during liver regeneration and repair, particularly following partial hepatectomy, liver injury and liver transplantation, is of great clinical significance. Based on an analysis of research articles from the past 20 years, the role of immunomodulation in liver regeneration, given the liver’s central function as an immune organ, requires further in-depth research and exploration.

Biographies

Tongjie Xu is a PhD candidate in the Department of Hepatopancreatobiliary Surgery and a physician in the Department of Vascular Surgery at the Affiliated Hospital of Southwest Medical University. He has been focusing on liver and vascular diseases for many years and has published numerous SCI articles and Chinese core articles.

Dan Li is a master’s degree student, graduated from Southwest Medical University. She specializes in orthopedics, spinal cord injury rehabilitation and liver rehabilitation, and has published numerous SCI articles and Chinese core articles.

Funding Statement

Southwest Medical University School Project [2024ZKY022].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

In this study, data sharing is not applicable as no new data were generated. The datasets utilized originated from publicly available resources.

Ethics approval statement

All data analyzed in this study were obtained from published literature and did not involve patient privacy or require ethical approval.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2025.2524249