This study employed bibliometric analysis to investigate signaling pathways in SPEM pathogenesis in the Web of Science Core Collection (WoSCC) from its inception until June 8, 2025. The search combined SPEM-related terms (e.g., “spasmolytic peptide expression metabolism,” “SPEM,” “TFF2”) with signaling pathway keywords (e.g., “signaling pathway,” “signal transduction”) using the Boolean operator “AND.” Only English-language articles were included, while non-research publications (e.g., reviews, editorials, conference abstracts, letters) were excluded. The complete search strategy is detailed in Supplementary Table 1. Two researchers independently screened 97 publications, excluded 8 irrelevant records, and ultimately included 89 articles for analysis (Figure 1). The data were exported from WoSCC and normalized to ensure consistency.

The data were processed via Microsoft Excel 2016 for database management and annual publication analysis, and the journal metrics were sourced from the Web of Science Journal Citation Reports. Bibliometric analyses were conducted via VOSviewer 1.6.20 and CiteSpace 6.4.R1. Data were cleaned to standardize terms (e.g., unifying “human spasmolytic polypeptide” and “polypeptide-expressing metaplasia” to “SPEM”) and abbreviations. VOSviewer creates network, density, and overlay maps to visualize relationships among authors, institutions, and keywords. Fractional counting was applied to assess collaboration strength, with a maximum of 25 authors per document. In CiteSpace, centrality (a metric ranging from 0 to 1) was used to identify pivotal nodes (e.g., publications, keywords, or authors) that function as bridges between research clusters, with values ≥0.1 indicating high interdisciplinary or conceptual significance. The CiteSpace settings included a time span of 1998 - 2025, year slices of 1, data cropping via the minimum spanning tree algorithm and path simplification network, and selection criteria of G value = 25. This approach enabled a detailed evaluation of research trends, key collaborations, and influential publications in the field of signaling pathways in SPEM pathogenesis.

Annual publications increased steadily from 1-3 (1998-2011) to a peak of 8 in 2023 (Figure 2A). The H-index (a measure of both productivity and citation impact, where a value of 6 means 6 publications each cited at least 6 times) showed similar growth, reaching 6 in 2023. Total citations (sum of the times cited, SOTC) peaked in 2004 (323), 2012 (522), and 2021 (347). Recent years (2023-2024) exhibited higher output but lower citations, consistent with expected citation lags. Notably, 2012 showed concurrent peaks in publications (6), H-index (5), and citations (522). Country-level analysis (Figure 2B) demonstrated the USA, China, and Japan as dominant contributors. China exhibited particularly rapid growth. The UK maintained consistent output, while Spain showed remarkable recent growth.

Our analysis of 89 publications from 56 journals revealed a distinct core-periphery distribution in research output. Notably, Gastroenterology emerged as the leading journal, contributing the highest number of articles (n=9, 10.11%) and maintaining the highest impact factor among the surveyed publications. This dominance underscores its pivotal role in disseminating influential research within the field. High-impact journals like Gut (IF = 23.1) and Cancer Research (IF = 12.5) publish fewer but highly cited articles, driving breakthroughs (Tables 1, 2). Knowledge graph analyses reveal multidisciplinary clusters (e.g., medicine-math, ecology-earth sciences), with Gastroenterology and Gut frequently cited, reflecting SPEM research’s integration with molecular biology and genomics. The dual-map overlay technique identifies influential journals in the field by analyzing citation relationships between source publications and their referenced works. Biplot analysis highlights molecular biology’s internal circulation, with journals such as Gastroenterology, Gut and Cancer Research being the main sources of knowledge (Figure 3). Future efforts should leverage interdisciplinary potentials by publishing in high-impact cross-field journals to bridge basic-clinical gaps and maximize knowledge value.

The multinational collaboration network included 221 institutions across 21 countries, yielding 89 publications. Productivity analysis revealed marked geographic disparities: the United States led with 41 publications (33.06%), focusing on TFF2-mediated mucosal repair and neoplastic transformation in SPEM pathogenesis (44–46). China follows with 20 studies (16.13%), emphasizing traditional medicine interventions (47) and clinicopathological correlations (48). Japan contributes 17 publications (13.71%), specializing in H. pylori pathogenesis (49). Germany (10, 8.06%) contributed seminal works on mucosal repair–pathology transitions (50, 51) (Table 3). CiteSpace analysis identified the U.S., China, Germany, Japan, the U.K., and Italy as pivotal ‘bridge nations’ (median centrality ≥0.10; Figure 4A). Literature with high intermediary centrality typically serves as a key link between two fields and is referred to as a “turning point” in CiteSpace, potentially leading to transformative discoveries and acting as a bridge. Despite this, the collaboration network exhibited a sparse core-periphery structure (density=0.1107 after pruning), with intensive cooperation concentrated among the U.S., Germany, Japan, and China, whereas low-income regions remained underrepresented. Institutional analysis (Figure 4B) highlighted academic “silos”: 60% of the top-active institutions were U.S., yet cross-border collaborations accounted for only 18% of the output, often constrained by short-term funding mechanisms. This fragmented landscape underscores the untapped potential for leveraging geographic strengths through structured multinational consortia.

Figure 4C presents a country-specific heatmap of research priorities in signaling pathways underlying SPEM pathogenesis, visually complementing our global bibliometric trends analysis. Integrated VOSviewer/CiteSpace analysis generated radar charts that quantify research emphasis across five thematic axes: (1) TFF2/SPEM molecular biology, (2) Helicobacter pylori pathogenesis mechanisms, (3) metaplasia-dysplasia-carcinoma progression, (4) mucosal repair/regeneration pathways, and (5) therapeutic targeting and apoptosis regulation.

The visualization reveals distinct national research fingerprints: The United States dominates axes 1 and 3, reflecting its pioneering work in TFF2-mediated neoplastic transformation models. China’s pronounced axis 5 profile aligns with its unique focus on phytochemical modulation of apoptotic pathways in SPEM. Japan’s axis 2 prominence confirms its continued leadership in H. pylori-related premalignant lesion studies, while Germany’s axis 4 specialization highlights its expertise in mucosal wound healing responses.

Notably, secondary research hubs (Australia, U.K., Italy, Singapore) exhibit concentrated but impactful contributions - particularly in emerging areas like single-cell transcriptomic mapping of SPEM (Australia) and microbiome-metaplectic niche interactions (Singapore) - forming critical interdisciplinary bridges in our CiteSpace-derived collaboration network. This core-periphery structure, quantitatively identified through betweenness centrality metrics, underscores the evolving global research ecosystem in SPEM pathophysiology.

A total of 719 authors have contributed to research on signaling pathways involved in the development and regulation of SPEM, with 85 authors publishing two or more articles. GOLDENRING JR leads with the highest number of publications (n = 10), followed by MILLS JC and OSHIMA M (n = 6 each), and OSHIMA H (n = 5) (Table 4). To analyze collaboration patterns, we constructed an author network using the 65 authors who published at least two papers (T ≥ 20) (Figure 5A). This knowledge graph highlights partnerships among high-frequency authors. The largest and most prominently colored group in Figure 5A consists of GOLDENRING JR and MILLS JC, underscoring their significant contributions to understanding the signaling pathways involved in SPEM pathogenesis. The second-largest group includes OSHIMA M and BUSADA JT.

Co-citation analysis of 3,430 authors (Figure 5B) further revealed three thematic domains among 75 influential scholars (citation frequency ≥5): (1) the Hormonal Regulation Group (Cidlowski JA, Busada JT) focused on glucocorticoid signaling in mucosal differentiation, (2) the Metaplastic Transition Group (Mills JC, Petersen CP) investigating SPEM lineage mechanisms, and (3) the Microenvironment Group (Goldenring JR, Peek RM) studying H. pylori and stromal interactions, with Goldenring JR emerging as the most interconnected researcher bridging multiple groups.

Keywords serve as a synthesis of research themes, where high-frequency terms reflect hotspots and high-centrality terms denote pivotal conceptual bridges. The density map analysis of 629 keywords (Figure 6A) revealed “cancer” as the dominant term (n=35, 5.56%), followed by “Helicobacter-pylori” (n=15, 2.38%), “stem-cells” (n=15, 2.38%), “differentiation” (n=14, 2.23%), and “metaplasia” (n=14, 2.23%), highlighting the field’s strong focus on SPEM’s role in gastric carcinogenesis, particularly through H. pylori-driven chronic inflammation and cellular reprogramming. The prominence of “stem-cells” and “differentiation” underscores the importance of cellular plasticity in SPEM development, while the high frequency of “metaplasia” reflects its critical position as a precancerous transition in the Correa cascade. This keyword distribution suggests that current research prioritizes understanding the molecular mechanisms linking SPEM to gastric cancer, with an emphasis on infection-related pathways, stem cell dynamics, and metaplastic progression, while also indicating potential gaps in translational applications such as biomarkers and targeted therapies (Table 5). Centrality analysis reveals “expression” (0.61) and “Helicobacter pylori” (0.4) as core hubs in SPEM research, framing two key dimensions: molecular mechanisms of gene regulation (particularly TFF2 and MIST1 pathways) and H. pylori-driven pathogenesis. These nodes interconnect multiple research clusters, reflecting the field’s dual focus on transcriptional control of metaplasia and infection-mediated carcinogenesis in gastric mucosa. The high centrality of “expression” marks the shift from histological characterization to mechanistic studies of cellular reprogramming, while maintaining H. pylori as the predominant etiological factor in SPEM development (Table 6).

The co-occurrence network was resolved into five thematic clusters, each representing distinct research dimensions (Figure 6B, Table 5). Cluster 1 (red), dominated by “expression” and “identification,” focused on molecular mechanisms of gene regulation, particularly transcriptional control in SPEM development. Cluster 2 (green) centered on cellular plasticity, featuring key terms like “stem-cells,” “metaplasia,” and “chief cells,” highlighting stem cell-driven reprogramming in gastric mucosa. Cluster 3 (blue) emphasized clinical pathology, with “intestinal metaplasia,” “carcinogenesis,” and “inflammation” underscoring the progression from H. pylori infection to premalignant lesions. Cluster 4 (brown–green) captured tissue-specific dynamics, including “stomach” and “differentiation,” while Cluster 5 (purple), anchored by “cancer” and “gastric metaplasia,” delineated the transition from metaplasia to malignancy. This clustering reveals the field’s multidisciplinary approach, spanning molecular, cellular, and clinical investigations of SPEM pathways.

The CiteSpace-derived keyword time-zone map and Burst Keywords visualized the temporal evolution of research on signaling pathways associated with SPEM pathogenesis from 2004 to 2025 (Figures 6C, D). Early-phase clusters (2004–2010) were dominated by high-frequency terms such as “Helicobacter pylori”, “NF-κB”, and “gastric adenocarcinoma”, underscoring the initial focus on infection-triggered inflammatory pathways that initiate SPEM. Between 2011 and 2016, the emergence of “Wnt/β-catenin”, “Notch”, and “TFF2” signaled a mechanistic shift toward delineating the intracellular networks governing chief-cell transdifferentiation. Since 2017, a rapid expansion of terms including “single-cell RNA-seq”, “chief-cell plasticity”, “organoids”, “Lgr5+ stem cells”, and “YAP” has formed densely interconnected clusters, indicating that technological advances are now dissecting microenvironmental signaling crosstalk and cellular heterogeneity within SPEM lesions.

Our bibliometric analysis using VOSviewer and CiteSpace delineates the intellectual foundations and evolving trends in signaling pathways in SPEM pathogenesis. Co-citation network analysis identified highly cited references (≥10 citations) that have shaped the field, with seminal contributions including Nam et al. (2010), whose discovery of chief cells as SPEM progenitors (16 citations) established a cellular basis for metaplastic transformation, and Goldenring et al. (2010), whose conceptual framework redefined SPEM-intestinal metaplasia relationships (12 citations) (Table 7).

Citation burst detection (Figure 7) revealed Petersen et al. (2017) as the strongest burst (strength=3.65, 2018-2021), highlighting Wnt/β-catenin signaling in SPEM plasticity, while three contemporary studies - Willet et al. (2018) on Notch signaling, Burclaff et al. (2020) employing single-cell RNA sequencing, and Sung et al. (2021) focusing on clinical translation - demonstrate sustained citation surges projected through 2025. Notably, 70% of burst articles emerged post-2016, clustering around two cutting-edge themes: growth factor signaling in mucosal repair (4/10) and molecular regulation of stem cell fate (3/10).

Temporal analysis uncovered a paradigm shift from early histopathological characterization (1992-2004) to contemporary mechanistic dissection (2016-present) in SPEM pathogenesis, with Gastroenterology serving as the predominant journal (5/10 top-cited articles). This progression from phenotypic observation to pathway-level understanding reflects the maturation of SPEM research into an integrated “phenotype-signaling-translation” framework, offering novel insights into gastric carcinogenesis.

This study employs bibliometric analysis combined with visualization techniques to preliminarily examine the current landscape of signaling pathways in SPEM pathogenesis. The evolution of research focus from an initial phase of descriptive pathology (1998–2011), which primarily established the clinical correlates of SPEM, to a current era of mechanistic inquiry (2012–present) aligns with broader trends in biomedical science. This shift has been propelled by the widespread adoption of single-cell technologies and multi-omics approaches, which enable the deconvolution of cellular heterogeneity, the construction of high-resolution spatiotemporal maps of the gastric mucosa, and the systematic elucidation of the molecular mechanisms driving SPEM pathogenesis (21, 52, 61). The observed publication growth (peak of 8 in 2023) coupled with a relatively modest H-index (6) suggests an expanding but still maturing field, where increased research activity has yet to produce proportionally high-impact breakthroughs. This pattern may reflect the inherent complexity of SPEM pathophysiology and the technical challenges in studying gastric mucosal reprogramming.

Journal analysis reveals Gastroenterology’s central role (10.11% of publications), underscoring its position as the primary forum for SPEM research. However, the limited presence in high-impact clinical journals points to a critical translational gap. This disparity likely stems from both the fundamental nature of current SPEM investigations and the challenges in connecting molecular mechanisms to clinical applications.

Geographic distribution shows concentrated expertise in the U.S., China, and Japan - nations with well-established gastroenterology research ecosystems. While these countries serve as important bridges in collaboration networks (centrality ≥0.10), the overall sparse connectivity (density=0.1107) suggests untapped potential for international synergy. The emergence of specialized author clusters, particularly around Goldenring JR and Mills JC’s work on chief cell plasticity, has been instrumental in defining current paradigms. However, the field would benefit from broader participation to foster innovation and diversify research perspectives.

These findings carry important implications for future research directions. First, the development of structured international consortia could accelerate progress by combining complementary expertise. Second, targeted efforts to bridge basic and clinical research could unlock therapeutic potential. Finally, strategic integration with related fields, particularly cancer stem cell biology and mucosal immunology, may yield novel insights into SPEM pathogenesis.

The co-citation network analysis has delineated the foundational knowledge structure of SPEM research, revealing two pivotal intellectual pillars. The first pillar comprises seminal works establishing the cellular basis of SPEM, most notably Nam et al.’s identification of chief cells as metaplastic progenitors (62) (16 citations) and Goldenring et al.’s conceptual framework for SPEM-intestinal metaplasia transitions (16) (12 citations). These studies provided the histological and conceptual foundation for understanding metaplastic transformation in gastric mucosa.

The second pillar consists of mechanistic studies that have driven recent advances, as evidenced by citation bursts. The strongest burst (Petersen et al. (63); strength=3.65) reflects the field’s focus on Wnt/β-catenin signaling in SPEM plasticity, He et al (21). elucidated that the CagA protein from H. pylori stabilizes TERT protein by inhibiting its SYVN1-mediated ubiquitination, leading to TERT accumulation in chief cells. The accumulated TERT then functions as a co-activator for the β-catenin transcriptional complex, resulting in the hyperactivation of the Wnt/β-catenin signaling pathway. This sustained activation directly promotes the dedifferentiation of mature chief cells into SPEM cells, establishing a direct molecular link between bacterial infection and metaplasia initiation. while contemporary bursts (Willet et al. (64); Burclaff et al. (65); Sung et al. (66)) highlight three critical research fronts: the molecular circuitry of paligenosis, wherein a transient state of mTORC1 inhibition and autophagic-lysosomal activation enables the de-differentiation of mature cells into a proliferative metaplastic state; the cellular origin of pre-neoplasia, with lineage-tracing evidence establishing post-mitotic chief cells as the primary source of SPEM, fundamentally reshaping models of gastric carcinogenesis; and the pathogenic transition from reparative to pre-malignant metaplasia, driven by persistent injury signals that sustain mTORC1-driven proliferation and suppress cellular re-differentiation pathways. Notably, 70% of high-burst publications emerged post-2016, clustered around mucosal repair mechanisms (40%) and stem cell fate determination (30%), indicating the field’s current trajectory toward molecular-level understanding.

This knowledge evolution follows a clear temporal pattern, transitioning from early histopathological characterization (1992-2004) to contemporary pathway dissection (2016-present), with Gastroenterology serving as the primary dissemination venue (50% of top-cited articles). While this progression from histopathology to molecular dissection has advanced the field, resolution of cellular origin controversies remains critical for fully understanding SPEM’s role in gastric cancer.

Through systematic analysis of keyword co-occurrence and temporal evolution patterns, our study delineates the dynamic landscape of global research into the signaling pathways underlying SPEM pathogenesis. The keyword density map reveals three predominant research axes that have shaped the field’s development: gastric carcinogenesis (represented by high-frequency terms “cancer” and “metaplasia”), cellular reprogramming mechanisms (“stem-cells” and “differentiation”), and infection-driven pathogenesis (“Helicobacter-pylori”). These core themes are interconnected through pivotal conceptual bridges, particularly gene expression regulation (centrality=0.61) and H. pylori interactions (centrality=0.4), which serve as critical nodes linking molecular mechanisms with pathological outcomes.

The co-occurrence network analysis resolved these research themes into five distinct yet interconnected clusters, demonstrating the field’s multidisciplinary nature. Cluster-level examination shows a clear progression from fundamental molecular investigations (gene regulation and transcriptional control) through cellular plasticity studies to clinical pathology applications.

The structural characteristics of SPEM research indicate that this field is currently in a transitional phase, evolving from phenomenological descriptions toward an integrated understanding of gastric mucosal transformation signaling networks, while still lacking a mature theoretical framework. Persistent controversies regarding cellular origins (isthmus stem cells vs. chief cell transdifferentiation) and key driving pathways (22) highlight fundamental challenges in mechanistic elucidation. Our analysis reveals that with the application of novel technologies like single-cell sequencing, recent research trends have gradually shifted toward favoring the stem cell theory (67), although the transdifferentiation hypothesis maintains its explanatory power in specific experimental models. This theoretical divergence is reflected in our co-citation network analysis, demonstrating the formation of distinct research clusters around stem cell-related pathways (e.g., Wnt/Notch) versus transdifferentiation-associated signals (e.g., mTOR). However, our theory-neutral approach also uncovered nascent efforts to bridge this divide, suggesting that the two mechanisms may not be mutually exclusive. To objectively present this complex landscape, we employed a theory-neutral term extraction approach combined with temporal evolution analysis and multidimensional visualization techniques, striving to comprehensively capture the research dynamics in this field.

Temporal mapping of keyword emergence reveals three characteristic phases in the field’s evolution. The early phase (2004-2010) focused predominantly on infection-induced inflammatory pathways, particularly H. pylori-mediated NF-κB activation (68). A transitional phase (2011-2017) witnessed growing emphasis on intracellular signaling cascades, including Wnt/β-catenin (21) and Notch pathways (60). Most recently (2018-2025), the field has embraced advanced single-cell technologies and microenvironmental analyses, as evidenced by the emergence of terms like “single-cell RNA-seq”, “organoids”, and “YAP signaling”. Building on this technological evolution, a paradigm shift is now underway in understanding SPEM pathogenesis, moving from a reductionist focus on linear pathways to an integrative appreciation of spatiotemporal network dynamics. This evolution in research focus, as revealed by the keyword mapping, has crystallized into a new paradigm: the understanding of SPEM pathogenesis has now shifted from a linear pathway model to a dynamic spatiotemporal network paradigm. Reflecting the technologies emblematic of the most recent phase, integrated data from single-cell RNA-seq and spatial transcriptomics are delineating a complex signaling geography within SPEM lesions. Studies consistently report a compartmentalization where the lesion core is dominated by stress-responsive pathways like the IFN-γ/STAT1 axis (69), which promotes epithelial proliferation and suppresses immune cell infiltration. In contrast, the periphery is enriched in fate-determining signals such as Wnt (21, 70) and BMP (71, 72), which repress chief cell differentiation genes and drive a progenitor-like transcriptional program. Furthermore, the use of organoid models, another hallmark of this period, has enabled temporal analysis through live imaging, defining a critical sequence of events: a transient Notch pulse activates downstream effectists like Hes1 to launch the dedifferentiation of chief cells (59), while sustained EGFR signaling through its MAPK effector pathway is required to maintain the mucinous metaplastic phenotype (73). This refined spatiotemporal framework, a direct product of the field’s technological maturation, underscores the inability of earlier, static models to explain the disease process and provides a mechanistic rationale for therapeutic strategies that target specific signaling nodes based on their spatial context and temporal function.

The evolving hotspot patterns demonstrate how technological advancements have progressively enabled deeper investigation of SPEM pathogenesis, from initial histopathological descriptions to current single-cell level analyses. This trajectory underscores the field’s ongoing transformation into a sophisticated, multidimensional research domain that integrates molecular, cellular, and microenvironmental perspectives on gastric mucosal transformation. Future research directions should aim to strengthen connections between these established knowledge domains while addressing the identified translational opportunities.

SPEM pathogenesis initiates through coordinated dysregulation of inflammatory signaling pathways that drive chief cell dedifferentiation. Sustained exposure to inflammatory stimuli like H. pylori infection activates NF-κB and STAT3 signaling in mature chief cells (74), leading to epigenetic silencing of master differentiation transcription factors including MIST1 and PGC (59, 67). This reprogramming is amplified through oxidative stress pathways, where reactive oxygen species activate the NRF2-HO-1 axis (58), further promoting the expression of metaplastic markers such as TFF2 and CD44v9. Single-cell transcriptomic analyses reveal that IL-11/STAT3 signaling (75) specifically orchestrates the transition from quiescent chief cells to proliferative SPEM precursors through sequential suppression of mature zymogenic gene programs and activation of progenitor-like transcriptional networks.

The transition to established SPEM involves convergent activation of developmental signaling pathways that lock cells in a metaplastic state. Wnt/β-catenin signaling emerges as a central regulator, with recent studies demonstrating that H. pylori CagA protein stabilizes TERT to potentiate β-catenin transcriptional activity (21). Simultaneously, YAP/TAZ signaling responds to biomechanical cues from the stiffening microenvironment, driving proliferation while suppressing apoptosis through regulation of anti-apoptotic proteins (57). This mechanosensitive signaling interacts with Wnt pathway components to create a self-reinforcing circuit that maintains dedifferentiation. Complementing these pathways, BMP signaling (72) - normally responsible for promoting chief cell maturation - becomes suppressed, removing critical differentiation pressure and permitting metaplastic persistence.

At the transcriptional level, SPEM cells exhibit a distinct enhancer landscape that reinforces the metaplastic program. Epigenomic profiling reveals super-enhancer reorganization around key transcription factor genes including SOX9 and CDX2 (56), which collaborate to maintain the SPEM transcriptional identity. These enhancer alterations are mediated through the coordinated action of inflammatory and developmental signaling pathways, with STAT3 directly binding to and remodeling enhancer regions controlling SPEM-associated genes (75). The resulting epigenetic state creates a stable transcriptional memory that persists even after removal of initial inflammatory triggers, explaining the irreversible nature of established SPEM lesions.

Metabolic reprogramming and microenvironmental crosstalk constitute the third pillar of SPEM maintenance. mTORC1 activation coordinates autophagic flux and lipid metabolism to support the bioenergetic demands of rapidly dividing SPEM cells (76). This metabolic adaptation interfaces with inflammatory signaling through mitochondrial ROS production, which further sustains NF-κB activation (58). The metaplastic epithelium actively remodels its microenvironment through secretion of IL-33 and other alarmins that recruit and polarize type 2 innate lymphoid cells and M2 macrophages, creating a pro-metaplastic inflammatory niche (58). Additionally, mesenchymal cells respond through aberrant PKA signaling (77), secreting factors that promote epithelial hyperplasia. This intricate network of epithelial-stromal-immune interactions creates a resilient signaling ecosystem that sustains SPEM and presents challenges for therapeutic intervention, necessitating multi-target approaches that address both cell-autonomous and non-autonomous signaling mechanisms.