The Pathogenesis and Therapies of Acute Pancreatitis: A Bibliometric Analysis from 2003 to 2025.

Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that manifests as acute abdominal pain. 1 Primarily caused by alcohol, gallstones, and hyperlipidemia, AP is characterized by rapid progression, frequent complications, prolonged hospitalization, and elevated morbidity and mortality. 2–4 Although typically a mild and self-limiting disease, approximately 20% of patients progress to severe AP, predisposing them to systemic inflammatory response syndrome. 5 This severe form precipitates critical organ damage, substantially impairing quality of life and augmenting mortality risk. 6 The pathogenesis remains incompletely understood. Consequently, extensive research continues to explore AP pathogenesis and targeted therapies using appropriate animal models. 7 , 8 Bibliometric analysis constitutes a quantitative methodology for evaluating scientific literature. 9 , 10 Through statistical examination of publications on specific topics, this approach enables the identification of research hotspots and trends while facilitating comparative assessment of contributions across nations, institutions, journals, and authors. 11 The Web of Science database, extensively utilized in bibliometric research, permits multidisciplinary literature retrieval. 12 Visualization tools including VOSviewer and CiteSpace further enhance data interpretation. 13 , 14 In the field of pancreatic disorders, previous bibliometric analyses have largely centered on general summaries, including trends in necrotizing and autoimmune pancreatitis. 15 , 16 However, these research have primarily focused on specific clinical subtypes, whereas no dedicated quantitative synthesis has been performed on AP pathogenesis and therapy. Over the past two decades, substantial research has investigated AP pathogenesis. 7 , 17 Studies employing AP animal models have focused on elucidating underlying mechanisms, developing novel therapeutic agents, and evaluating treatment efficacy. 6 , 18 , 19 Although several published narrative reviews summarize current findings and advancements in AP, a quantitative and objective bibliometric analysis remains scarce. 20 , 21 Bibliometrics not only enables the analysis of collaboration networks but also facilitates the tracking of dynamic changes in research hotspots, thereby filling the gaps left by review articles. Accordingly, this study presents a comprehensive bibliometric analysis of AP pathogenesis and therapies from 2003 to 2025. Our research quantitatively identified key mechanisms, including oxidative stress, and evolving themes such as gut microbiota. We identify cerulein-rodent models as the dominant experimental paradigm for AP. Furthermore, we highlighted hotspots related to acinar cell death modalities and immune regulation, while also identifying innovative therapeutic strategies. These findings provide a methodological reference for model selection and suggest directions for novel interventions in future translational research.

From 2003 to 2025, 25,421 publications were initially identified through systematic database retrieval. Following exclusion of 10,798 non-article or non-English publications, 14,623 records underwent title and abstract screening against inclusion criteria, yielding 632 articles for bibliometric analysis ( Figure 1 ). Figure 1 Literature screening and selection flowchart. A flowchart detailing the literature screening process. Initially, 25,421 records were identified through Web of Science database searching. After screening, 14,623 records remained. Records excluded at this stage totaled 10,798, including meeting abstracts (5,023), review articles (2,678), letters (1,203), editorial material (932), proceeding papers (378), early access (97) and non-English publications (487). Further screening excluded 13,991 records, comprising clinical studies (7,627), studies on pancreatic cancer or chronic pancreatitis (3,188), in vitro studies and bioinformatics analysis (1,684) and others (1,492). Ultimately, 632 records were included in the bibliometric study. Flowchart of literature screening from 25,421 records to 632 included in study. Literature screening and selection flowchart. Annual publication output demonstrated progressive growth since 2017, culminating in a peak in 2024, accounting for 11.70% of total publications (R 2 =0.4465, p<0.001; Figure 2A ). The 2003–2016 exhibited a mean annual output of approximately 21 publications, with notable declines during 2010–2011 and 2012–2014, though cumulative publications maintained an upward trajectory ( Figure 2B ). Overall, citation counts exhibited an upward trend (R 2 =0.3443, p<0.01; Figure 2C ). Annual citation counts remained below 15 from 2003 to 2010, fluctuating moderately around 18 during 2011–2019. A marked surge occurred from 2019 to 2020, reaching peak citations in 2024 with sustained growth through 2021–2023. The H-index remained relatively stable at around 14 from 2003 to 2019, followed by a gradual decline in subsequent years ( Figure 2D ). The period following 2010 represents a phase characterized by heightened research productivity and substantial advances in understanding the pathogenesis of AP. Figure 2 Temporal publication trends in acute pancreatitis research (2003–2025). ( A ) Annual number of published articles ( B ) Cumulative number of published articles ( C ) Annual citation number of publications ( D ) Annual H index of publications. The image A shows a line graph with the x-axis labeled 'Year' and the y-axis labeled 'Number of annual publications'. It depicts data from 2003 to 2025, showing fluctuations with a peak in 2024. The image B shows a line graph with the x-axis labeled 'Year' and the y-axis labeled 'Number of cumulative publications'. It shows a steady increase from 2003 to 2025. The image C shows a line graph with the x-axis labeled 'Year' and the y-axis labeled 'Number of citations'. It shows a rise with a peak in 2024. The image D shows a line graph with the x-axis labeled 'Year' and the y-axis labeled 'H-index'. It shows stability around 14 from 2003 to 2019, followed by a decline towards 2025. Four graphs showing trends in publications, citations and H-index from 2003 to 2025. Temporal publication trends in acute pancreatitis research (2003–2025). ( A ) Annual number of published articles ( B ) Cumulative number of published articles ( C ) Annual citation number of publications ( D ) Annual H index of publications. There are ten most-cited studies from 2003 to 2025 (Web of Science data), with citations ranging from 164 to 264 ( Supplementary Table 1 ). All investigations focused exclusively on AP pathogenesis. Among these, six elucidated acinar cell pathobiology including impaired autophagy, trypsinogen activation, calcium signaling dysregulation, and endoplasmic reticulum stress. The remaining four addressed immune mediated mechanisms, predominantly neutrophil extracellular traps (NETs) and the STING signaling pathway. The global collaboration network comprised 22 countries connected through 74 links, organized into seven color-coded clusters based on partnership ( Figure 3A ). Notable contributors included the USA, China, England, Germany, Switzerland, and Japan. We present bibliometric indices including publication volume, H-index, total citations, and citations per publication for the five most productive nations ( Supplementary Table 2 ). China dominated publication output (n=335), followed by the USA (n=100). However, the USA achieved superior citation metrics, including the highest H-index (37), total citations (4965), and citations per publication (49.65), underscoring its leading influence alongside China in AP pathogenesis research. Sweden demonstrated exceptional citations per publication (41.07) despite lower publication volume. These findings confirm sustained global engagement in AP pathogenesis and therapies investigation. The institutional network encompassed 91 entities with 241 links ( Figure 3B ). Shanghai Jiao Tong University led in publication volume (n=49), whereas the US Department of Veterans Affairs and Veterans Health Administration VHA attained the highest H-index (18) and total citations (1348) (see Supplementary Table 3 ). The University of California System recorded the highest citations per publication (65.61). Figure 3 Collaborative networks analyses in acute pancreatitis research. ( A ) Country/region network ( B ) Institutional network ( C ) Author co-authorship network, ( D ) Keyword co-occurrence network. Node size corresponds to publication volume or keyword frequency. Inter-node linkage thickness denotes collaboration strength. The image A showing a country collaboration network diagram highlighting China and the USA as central nodes, with links to other countries like England, Germany and Japan. The image B showing an institutional network diagram with Shanghai Jiao Tong University as a central node, connected to various universities worldwide. The image C showing an author co-authorship network diagram with clusters of authors such as Lerch Markus M. and Sendler Markus. The image D showing a keyword co-occurrence network diagram centered around 'acute pancreatitis', with related terms like 'inflammation' and 'expression'. Each diagram illustrates collaboration strength through node size and linkage thickness. Diagrams of country, institution, author and keyword collaborations in acute pancreatitis research. Collaborative networks analyses in acute pancreatitis research. ( A ) Country/region network ( B ) Institutional network ( C ) Author co-authorship network, ( D ) Keyword co-occurrence network. Node size corresponds to publication volume or keyword frequency. Inter-node linkage thickness denotes collaboration strength. Over 3900 authors contributed to the publications. The co-authorship network comprised 62 researchers ( Figure 3C ), with Lerch Markus M. contributing the highest number of publications (n=16), followed by Sendler Matthias (n=14), Mayerle Julia (n=14), Wen Li (n=11), and Sutton Robert (n=11). Gukovskaya Anna S. demonstrated extensive collaboration with 32 authors. The 632 articles appeared in 218 journals. Supplementary Table 4 documents key metrics for the five most productive journals. Pancreas accounted for the highest publication volume (n=42), while Gastroenterology achieved peak total citations (2797), citations per publication (116.54), H-index (24), and IF (2023) (26.3). A total of 64 keywords with at least 14 occurrences were categorized into five thematic clusters (color-coded) ( Figure 3D ). The most frequent terms included “acute pancreatitis”, “inflammation”, “activation”, “expression”, and “nf-kappa-b”, Keywords denoting disease severity encompassed “injury”, “severity”, “severe acute pancreatitis”, and “acute necrotizing pancreatitis”. Terms related to pathogenesis featured “oxidative stress”, “autophagy”, and “trypsinogen activation”, whereas therapeutic interventions were represented by “inhibition” and “protection”. The top 21 keywords with strongest citation bursts showed intensities ranging from “rat” (highest intensity) to “sepsis” (lowest intensity) ( Figure 4 ). “Rat” demonstrated peak burst intensity of 9.71 during 2003–2010, while “cerulein-induced pancreatiti” reached 5.04 during 2003–2013. The period 2009–2018 witnessed the emergence of “acinar cell” with burst intensity of 5.03, reflecting deeper mechanistic investigations. Keyword burst detection identified emerging surges for “gut microbiota”, “autophagy”, “metabolism”, and “stress”, with strengths of 4.78, 4.58, 5.36, and 4.37 respectively, indicating a shift in research emphasis toward these themes. Figure 4 Temporal citation bursts of the 21 most prominent keywords (2003–2025). Red bars indicate high-burst periods, while green denotes baseline activity. The chart displays the top 21 keywords with the strongest citation bursts from 2003 to 2025. Each keyword is listed alongside its year of emergence, strength and the period of burst activity. Keywords include 'rat' with a strength of 9.71 from 2003 to 2010, 'cerulein induced pancreatiti' with 5.04 from 2003 to 2013 and 'neutrophil' with 4.18 from 2003 to 2005. Other keywords like 'lung injury' and 'dysfunction' show strengths of 6.62 and 6.08, respectively. The chart uses red bars to indicate high-burst periods and green for baseline activity. Emerging keywords such as 'gut microbiota', 'autophagy' and 'metabolism' show bursts extending to 2025, reflecting shifts in research focus. Chart of top 21 keywords with citation bursts from 2003 to 2025, showing strength and duration. Temporal citation bursts of the 21 most prominent keywords (2003–2025). Red bars indicate high-burst periods, while green denotes baseline activity. Manual extraction of modeling approaches was performed to further explore certain clusters within the keyword network, including “rats”, “caerulein”, and “l-arginine”. Experimental animals predominantly comprised rodents mainly rats and mice, with two porcine models also utilized. Modeling methodologies varied according to experimental objectives ( Figure 5A ). Cerulein induction via intraperitoneal injection represented the most prevalent approach (47.08%), with 50 μg/kg being the frequent dosage ( Figure 5B ). Notably, this high prevalence was associated with substantial academic impact. Among the ten most cited articles in our dataset, eight employed a cerulein induced rodent model, suggesting that this approach provides the foundational framework for mechanistic discoveries in AP. Administration typically involved 2–13 hourly injection. Severity was modulated by increasing injection frequency or dose without altering intervals, with 7 hourly injections being most frequent, followed by 10 injections. Figure 5 Induction methodologies for acute pancreatitis animal model. ( A ) proportion of modeling methods ( B ) Cerulein dosage distribution ( C ) Sodium taurocholate concentration profile. The total indicates the number of acute pancreatitis animal models. Unspecified dosages in included publications were recorded as NA. The image A shows a pie chart illustrating the proportion of modeling methods for acute pancreatitis. The chart includes 47.08 percent cerulein, 21.59 percent sodium taurocholate, 10.45 percent L-arginine, 9.75 percent others, 8.22 percent cerulein plus lipopolysaccharide and 2.92 percent pancreatic duct ligation, with a total of 718 models. The image B shows a pie chart detailing cerulein dosage distribution. It includes 53.85 percent at 50 micrograms per kilogram, 18.64 percent NA, 9.76 percent at 100 micrograms per kilogram, 9.76 percent others, 4.44 percent at 20 micrograms per kilogram and 3.55 percent at 50 milligrams per kilogram. The image C shows a pie chart of sodium taurocholate concentration profile. It includes 32.26 percent NA, 32.26 percent at 5 percent, 11.61 percent others, 9.68 percent at 3 percent, 7.10 percent at 4 percent and 7.10 percent at 3.5 percent. Pie charts: modeling methods, cerulein dosage, sodium taurocholate for acute pancreatitis. Induction methodologies for acute pancreatitis animal model. ( A ) proportion of modeling methods ( B ) Cerulein dosage distribution ( C ) Sodium taurocholate concentration profile. The total indicates the number of acute pancreatitis animal models. Unspecified dosages in included publications were recorded as NA. Sodium taurocholate retrograde pancreatic duct infusion constituted the second most frequent method (21.59%). The dosage of sodium taurocholate was 1 mL/kg, with 5% concentration being predominant, accounting for 32.26% ( Figure 5C ). Additionally, l-arginine overdose induced 10.45% of AP models, primarily through two intraperitoneal injections administered at one-hour intervals using doses of 4 g/kg (53.42%) or 2.5 g/kg (24.66%). Most cell models mainly originated from mice, with pancreatic acinar cells being predominant. Primary acinar cells (49.33%) and AR42J cell line (41.78%) constituted the majority ( Figure 6A ). The 266–6 cell line has only been gradually utilized in recent years, with a relatively small quantity (4.44%). The HPDE6-C7 cell line, which from human pancreatic ductal epithelial cells, accounts for 1.78%. Similar to animal models, cerulein was the primary stimulant, followed by cholecystokinin and taurolithocholic acid sulfate. The most commonly used concentrations of cerulein are 10 nM and 100 nM, with AR42J cells typically receiving exposures of 24 hours. 10nM cerulein is usually used to study the early events of AP, causing damage but with less cell death. However, 100nM cerulein induces significant pathological damage. Figure 6 Cell models in acute pancreatitis pathogenesis research (2003–2025). ( A ) Pancreas-related cell models ( B ) Immune cell models. The total indicates the number of cell models. The image A shows a pie chart illustrating the distribution of pancreas-related cell models in acute pancreatitis research. The chart indicates 49.33 percent primary pancreatic acinar cells, 41.78 percent AR42J cell line, 4.44 percent 266–6 cell line, 2.67 percent others and 1.78 percent HPDE6-C7 cell line, with a total of 225 models. The image B shows another pie chart depicting immune cell models. It shows 49.04 percent primary macrophage, 27.88 percent RAW 264.7 cell line, 12.50 percent primary neutrophil, 6.73 percent THP-1 cell line and 3.85 percent others, totaling 104 models. Two pie charts showing cell model distributions in acute pancreatitis research. Cell models in acute pancreatitis pathogenesis research (2003–2025). ( A ) Pancreas-related cell models ( B ) Immune cell models. The total indicates the number of cell models. In AP, the abnormal activation of immune cells is also of crucial importance. In immune cell models, macrophage models constituted the majority, including primary macrophages (49.04%) and the RAW 264.7 cell line (27.88%) ( Figure 6B ). Primary macrophages were predominantly isolated from bone marrow and peritoneal cavities. To model the secondary bacterial infection or systemic inflammatory response in severe AP. LPS is frequently employed to stimulate macrophages. The most commonly used concentration is 1 μg/mL, with a typical stimulation duration of 24 hours. Primary neutrophils (12.50%) were mainly sourced from rodent bone marrow and spleen. The human THP-1 cell line was infrequently used, accounting for 6.73%. Acinar cell death research exhibited dynamic temporal shifts ( Figure 7A ). Apoptosis dominated during 2003–2006, subsequently declining in relative contribution (R 2 =0.7758, P<0.05). The proportion of studies focusing on necrosis was higher in 2007–2018 compared with 2003–2006. Autophagy emerged as a significant focus from 2007 onward, peaking during 2019–2021 with beclin-1 and LC3 as principal molecular targets (R 2 =0.6968, p<0.05). And mitophagy investigations demonstrated progressive growth. Research on ferroptosis and pyroptosis was more frequently observed during 2022–2025. The NLRP3/gasdermin D axis represents a key pyroptosis pathway, while glutathione peroxidase 4 (GPX4) and ACSL4 are focal points in ferroptosis of AP. Figure 7 Temporal evolution of molecular mechanisms in acute pancreatitis pathogenesis (2003–2025). ( A ) Acinar cell death pathway dynamics ( B ) Immune cell signaling trajectory. The image A showing a bar graph illustrating the percentage trends of different cell death pathways over time. The x-axis is labeled 'Year' with intervals: 2003–2006, 2007–2010, 2011–2014, 2015–2018, 2019–2021 and 2022–2025. The y-axis is labeled 'Percentage' ranging from 0 to 100. The graph displays segments for necrosis, apoptosis, autophagy, pyroptosis and ferroptosis. The image B showing a bar graph depicting the percentage trends of immune cell types over the same periods. The x-axis is labeled 'Year' with the same intervals as image A. The y-axis is labeled 'Percentage' ranging from 0 to 100. The graph includes segments for neutrophils, macrophages, T cells and others. Two bar graphs showing percentage trends in cell death pathways and immune cell types from 2003 to 2025. Temporal evolution of molecular mechanisms in acute pancreatitis pathogenesis (2003–2025). ( A ) Acinar cell death pathway dynamics ( B ) Immune cell signaling trajectory. Immune cells investigations evolved substantially ( Figure 7B ). Neutrophil studies maintained stable prevalence, fluctuating around 40%, transitioning from infiltration to NETs. From 2015 to 2025, the research focus shifted toward macrophage studies, with M1/M2 polarization and metabolic reprogramming emerging as prominent themes. T cell investigations progressively developed during 2011–2025, particularly regarding Treg/Th17 balance. Dendritic and mast cells constituted minor proportions. The relationship between gut microbiota and AP has been increasingly established. Early studies identified microbial translocation causing severe AP infections. Metagenomics later revealed dysbiosis, prompting probiotic interventions. Compared with healthy controls, the relative abundance of probiotic is significantly depleted in fecal samples from AP patients. These microorganisms represent potential therapeutic targets, primarily through modulation of inflammatory cascades in AP ( Figure 8 ). Specifically, Bacteroides uniformis, Bifidobacteria animalis, Lactobacillus, Akkermansia , and Parabacteroides exert protective effects predominantly via metabolites including short-chain fatty acids (SCFAs), tryptophan metabolites (norharman), lactate, bile acid metabolites (taurine), and derived proteins. Clostridium butyricum attenuates proinflammatory cytokine release through the AMPK/nf-kappa-b pathway. Akkermansia muciniphila further reduces macrophage and neutrophil infiltration through its membrane proteins and modulates gut microbiota composition. Moreover, Lactobacillus ameliorates intestinal and pancreatic injury via NOD2-dependent regulation of Paneth cell function. Prebiotics also demonstrates therapeutic effects in AP ( Figure 8 ). After prebiotic administration, the gut microbiota undergoes alterations, with an increase in probiotic and a reduction in pathogenic bacteria. Immune modulation and oxidative stress represent the primary targets. Inulin suppresses M1 macrophage polarization by enriching intestinal Akkermansia abundance to promote SCFAs production, whereas oligosaccharides ameliorate AP through oxidative stress alleviation. Figure 8 Therapeutic mechanisms of probiotic and prebiotics in acute pancreatitis. Bacteroides uniformis, Bifidobacterium animalis, Lactobacillus, Akkermansia, Clostridium butyricum and Parabacteroides modulate immune responses via the gut-pancreas axis. Inulin and oligosaccharides, as prebiotics, alleviate acute pancreatitis by directly or indirectly inhibiting M1 polarization and oxidative stress respectively. Created with BioRender. The illustration depicts the gut-pancreas axis and the role of probiotics and prebiotics in acute pancreatitis. On the left, a human figure shows the pancreas and intestines with an arrow indicating bacterial translocation. The right section details the gut lumen and tissue interactions. Probiotics like Bacteroides uniformis, Bifidobacterium animalis, Lactobacillus and Akkermansia are shown interacting with enterocytes, producing metabolites such as taurine, lactate, norharman and short-chain fatty acids. Akkermansia's membrane protein influences paneth cells and macrophage infiltration, while Clostridium butyricum and Parabacteroides are linked to proinflammatory cytokine release and neutrophil infiltration. Prebiotics like inulin and chitosan oligosaccharides are depicted as interventions, reducing M1 polarization and oxidative stress. The diagram highlights the balance between probiotic and pathogenic bacteria in acute pancreatitis management. Gut-pancreas axis: bacterial movement, probiotics, prebiotics, pathogens in acute pancreatitis. Abbreviations : NETs, Neutrophil extracellular traps; SCFAs, short chain fatty acids. Therapeutic mechanisms of probiotic and prebiotics in acute pancreatitis. Bacteroides uniformis, Bifidobacterium animalis, Lactobacillus, Akkermansia, Clostridium butyricum and Parabacteroides modulate immune responses via the gut-pancreas axis. Inulin and oligosaccharides, as prebiotics, alleviate acute pancreatitis by directly or indirectly inhibiting M1 polarization and oxidative stress respectively. Created with BioRender. Publications addressing nanotherapy and traditional Chinese medicine (TCM) have increased in recent years. Nanotherapy enables targeted delivery, stimuli responsive release, and synergistic effects. Current nanotherapy for overcoming the barrier between blood and pancreas primarily involves high-affinity binding to type III collagen within the barrier or utilizes macrophage membrane coating techniques. The majority of nanotherapy targets mitochondrial dysfunction and inflammatory regulation, and other studies address calcium signaling pathway, oxidative stress, and acinar cell death modalities. A tuftsin conjugated nanoplatform DSSM@TN NPs targets the P2X7 mediated Nrf2/PINK1 pathway, enhancing mitophagy induction while suppressing NLRP3 expression. Moreover, nanoparticles pHA@IBNCs are composed of epigallocatechin gallate, IL-22, bovine serum albumin, and phenylboronic acid-modified hyaluronic acid. These nanoparticles ameliorate AP through triple mechanisms: ROS scavenging, proinflammatory cytokine suppression, and intestinal epithelial regeneration. TCM encompasses Dachengqi Decoction and Qingyi granules. These formulations include bioactive compounds such as emodin, berberine, and curcumin. TCM exerts multiple therapeutic effects through three primary mechanisms: inflammation modulation, improvement of intestinal homeostasis, and cell death pathway intervention. These involve inhibition the polarization of M1 macrophages and the activation of NLRP3 within inflammation modulation; preservation of intestinal mucosal barrier integrity and regulation of gut microbiota for intestinal homeostasis; attenuation of pyroptosis in acinar cells.

In this study, data were retrieved from the Web of Science Core Collection (WoSCC) database. WoSCC is widely recognized for its curated coverage of rigorously selected journals, making it the most frequently utilized database in bibliometric research. The retrieval strategy was TS = “acute pancreatitis”. Publications were restricted to English language and covered the period from January 01, 2003, to May 12, 2025. All the relevant studies were evaluated in three stages by three authors independently, and any conflicts were thoroughly discussed with the corresponding author. Publications from the Science Citation Index-Expanded (SCI-E) were screened by evaluating titles and abstracts, with full text review when necessary. Inclusion criteria comprised the following: (1) Original research articles (excluding review, letter, editorial material, meeting abstract, proceeding paper, and early access); (2) Studies utilizing animal models of AP; (3) Research focusing on AP pathogenesis, therapies, and associated mechanisms. Eligible articles were downloaded and exported in multiple formats. A standardized extraction template was developed in Microsoft Excel 2019, capturing: (1) Publication metadata including title, authors (first author and affiliated country), total citations, citations per publication (total citations/total publications), journal name, 2023 journal impact factor (IF), and H-index (defined as the number of papers with citation number > or = H); 22 (2) Specific pathogenic mechanisms of AP; (3) Therapeutic agents with corresponding efficacy (effective/ineffective/exacerbating) and mechanistic pathways. (4) The animal models or cell models utilized in the experiment, along with the methods employed for model establishment. For included studies, the animal species, inducing modeling agent, dosage, and administration route, were manually curated from the “Materials and Methods” sections. The frequencies and percentages of each modeling method were then calculated from the extracted data. For accurate bibliometric analysis, a comprehensive data preprocessing protocol was applied. First, no duplicate records were identified among the included documents using CiteSpace (version 6.1 R6). Second, author names and institutional affiliations were standardized to resolve inconsistencies in naming conventions. Third, synonymous keywords including morphological variants and spelling variations were merged to optimize clustering. Finally, we confirm all included documents had complete metadata. Bibliometric visualization was performed using VOSviewer (version 1.6.20), CiteSpace, and GraphPad Prism (version 9.1.0). VOSviewer generated co-occurrence networks to map academic collaborations and keyword associations, with clustering analysis achieved through color-coded nodal groupings. 23 Node size reflected publication volume, while line thickness indicated connection strength. CiteSpace identified research hotspots via keyword burst detection. GraphPad Prism conducted supplementary quantitative analyses. Moreover, linear regression analysis was used to evaluate the temporal trend. The coefficient of determination (R 2 ) and p value were calculated to assess the fitness and significance of the trend. A P value below 0.05 was considered statistically significant.

This bibliometric analysis synthesizes two decades of research, charting the evolving landscape of pathogenesis and therapies in AP. Regarding mechanisms, the field is transitioning from apoptosis to emerging forms of acinar cell death, most notably ferroptosis and pyroptosis. Moreover, immune modulation is gaining attention including NETs and macrophage polarization. On the therapeutic front, gut microbiota and nanotherapy are attracting growing interest. Despite considerable progress, critical knowledge gaps persist. The cerulein induced rodent model is widely adopted but inadequately recapitulates human AP. This model fails to reproduce the early stages of systemic inflammatory response syndrome and organ failure, as well as late infectious complications. Clinical translation of ferroptosis or pyroptosis inhibitors remains restricted to preclinical stages. Furthermore, high-quality trials of probiotics and nanotherapy in AP patients are lacking. We advocate for the prioritized development of advanced animal models that better mirror human AP and for focused efforts to explore nanotherapy and microbiota modulation, thereby bridging mechanistic discoveries and clinical applications.

This bibliometric analysis identified 632 publications related to AP pathogenesis and therapies from the Web of Science database, synthesizing research trends and hotspots. We found cerulein represents the most extensively utilized agent for establishing AP models. Ferroptosis and pyroptosis constitute predominant foci in acinar cell death modalities. NETs, macrophage polarization, and Treg/Th17 balance dominate immune cell investigations. Furthermore, gut microbiota modulation, nanotherapy, and TCM represent emerging investigational domains for AP treatment strategy. Notably, although author-level metrics such as publication count are useful for identifying prolific contributors, they largely reflect quantitative output rather than qualitative impact. Appropriate animal models facilitate elucidation of AP pathophysiology. 7 , 24 Our analysis revealed cerulein (47.08%), sodium taurocholate (21.59%), and l-arginine (10.45%) as predominant induction methods. Cerulein is a cholecystokinin analogue that acts with cholecystokinin receptors to activate some second messenger pathway, thereby affecting Ca2+ signaling, zymogen activation, and cell death in acinar cells. 25 , 26 The cerulein-induced pancreatitis model primarily elicits mild edematous pancreatitis with a favorable prognosis, which mirrors certain clinical features of the disease. However, this model rarely induces infections around the pancreas or distal organ injury, thereby failing to adequately recapitulate severe AP. Moreover, the pathological mechanisms involved do not encompass typical clinical etiologies of AP, such as biliary obstruction or alcohol toxicity. Sodium taurocholate induces acute biliary pancreatitis, which is the predominant clinical etiology of AP. 27 However, this invasive approach may contribute to elevated mortality subsequent to induction. 28 Conversely, the AP model induced by l-arginine requires only intraperitoneal injection, constituting a minimally invasive procedure. This model elicits extensive acinar cell necrosis with concomitant multiple organ injury, though controversy persists regarding whether organ damage represents secondary AP complications or direct l-arginine toxicity. 29 In reality, substantial physiological and pathological differences exist between humans and animal models. Most currently available animal models are associated with inherent limitations and predominantly simulate only the initial phase of AP, while poorly recapitulating the advanced stages of the disease. Therefore, modeling methodologies for AP require further refinement. Following the establishment of appropriate models, researchers subsequently elucidate cell death mechanisms in acinar cells. Ferroptosis and pyroptosis have recently emerged as active research areas in AP. Current research on ferroptosis and pyroptosis in AP remains predominantly at the preclinical stage, with inhibitors of both forms of cell death demonstrating promising efficacy in animal models. In a rat model, liproxstatin-1 was shown to ameliorate acute hypertriglyceridemic pancreatitis by suppressing ferroptosis. 30 GPX4 and ACSL4 constitute core ferroptosis regulators. During AP onset, ACSL4 expression is upregulated, whereas GPX4 is downregulated. 31 These ferroptosis related molecules have the potential to serve as novel biomarkers for AP. Pyroptosis of acinar cells was consistently observed following pancreatic toxin exposure both in vivo and in vitro. 32 Pyroptosis execution involves gasdermin D and NLRP3. Further research revealed that NLRP3 and gasdermin D collaboratively drive pyroptosis in acinar cells by forming membrane pores that release proinflammatory cytokines, a pivotal mechanism underlying the transition from localized to systemic inflammation. 32 A study employing network pharmacology and experimental validation revealed that Chaiqin Chengqi Decoction alleviates AP by targeting pyroptosis through inhibition of gasdermin D. 33 These findings highlight ferroptosis and pyroptosis offer potential therapeutic targets for AP. However, their clinical applications warrant further investigation. Furthermore, the role of immune cells in AP pathogenesis is indispensable. Wang et al observed that during the onset of AP, nf-kappa-b/HIF-1α axis activates fibroblasts via glycolytic reprogramming. 34 Activated fibroblasts overexpress CXCL1, driving neutrophil infiltration and the formation of NETs. 34 Macrophage polarization is also elucidated as a significant process in AP. In AP models and primary acinar cells induced by cerulein plus LPS, mixed-lineage kinase domain-like protein (MLKL) operates independently of receptor-interacting serine/threonine-protein kinase 3. 35 MLKL knockout reduces CXCL10 secretion, attenuating M1 macrophage polarization. 35 The Treg/Th17 equilibrium is critical for intestinal barrier integrity, as bacterial translocation to the pancreas necessitates barrier compromise. 36 Although Tregs attenuate inflammation, they concomitantly impair duodenal mucosal barrier function, facilitating bacterial translocation to necrotic pancreatic tissue. 37 Restoring gut–pancreas axis homeostasis represents a pivotal treatment strategy. Supplementation of probiotics and prebiotics may alleviate clinical symptoms in AP patients. A prospective randomized trial demonstrated that lactulose improves intestinal health in AP patients by enhancing SCFAs production and modulating gut microbiota. 38 However, another study reported that a multispecies probiotic preparation failed to reduce infectious complications in patients with severe AP and was associated with an increased mortality risk. 39 Fecal microbiota transplantation (FMT) is a first-line treatment for Clostridioides difficile infection and has been widely adopted due to its capacity to reshape the gut microbiota. A randomized controlled trial involving 60 participants demonstrated that FMT had no significant effect on intra-abdominal pressure or infectious complications in patients with AP. However, no serious adverse events were observed, indicating a favorable safety profile of FMT. 40 In summary, the optimal probiotic strains and dosage regimens for clinical management of AP require further investigation. Additionally, factors such as concomitant antibiotic use and procedural details of FMT may influence its efficacy, underscoring the need for more extensive and rigorous clinical studies. Nanotherapy enhances drug delivery efficiency and targeting specificity, while TCM as an adjunctive therapy not only exhibits a favorable safety profile but also effectively alleviates clinical symptoms. Both nanotherapy and TCM formulations primarily exert their therapeutic effects through shared pathways, including anti-inflammatory actions, antioxidant effects, and modulation of cell death modalities. Nanotherapy enables penetration of the barrier between the blood and pancreas and targeted delivery. TCM formulation mainly serves as an adjuvant therapy clinically. Numerous studies integrate TCM compounds with nanoparticles. For example, a double blind randomized trial in mild and moderate AP patients revealed that nanocurcumin reduces hospital length of stay and improves appetite. 41 However, challenges such as the potential risk of tissue damage associated with nanotherapy and the slow onset of efficacy of TCM remain to be further addressed. Our study has several limitations that should be acknowledged. First, the exclusive reliance on the SCI-E of WoSCC may have resulted in incomplete literature coverage, as relevant publications indexed in other databases such as PubMed and Scopus were not included. However, the Web of Science database remains a gold standard for bibliometric analyses due to its rigorous journal selection process and comprehensive citation data. Second, the restriction to English language publications means we may have overlooked potentially eligible studies published in other languages. Third, this article primarily focused on fundamental research related to AP, thereby paying limited attention to clinical study.