Idiopathic pulmonary fibrosis and interleukins: a bibliometric analysis [1999–2025]

Introduction

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial pulmonary disease of unclear cause, clinically defined by exertional dyspnea and a persistent dry cough (1,2). Globally, approximately three million individuals are affected by IPF, and both its incidence and prevalence continue to rise steadily (3-5). Although currently available drugs (e.g., pirfenidone, nintedanib) can delay disease progression to some extent, their overall efficacy remains limited and is often accompanied by adverse effects and substantial financial burden (6,7). A lung transplant is considered the only treatment capable of prolonging a patient’s life to some extent (8,9). Owing to the poor prognosis, heavy symptom burden and financial pressures, IPF imposes a profound negative impact on the quality of life of patients (10,11). Consequently, elucidating the biological mechanisms underlying IPF pathogenesis and developing additional therapeutic strategies remain urgent clinical and scientific priorities.

In recent years, the role of interleukins (ILs) in IPF has been the focus of increasing attention. A mounting body of evidence indicates that multiple ILs are intimately involved across the spectrum of IPF, spanning disease initiation, progression, diagnosis, and treatment, and may serve as emerging therapeutic targets. Aging represents a primary risk factor for IPF, and IL-11, a key component of the senescence-associated secretory phenotype (SASP), has been shown to promote multiple fibrotic processes in the lung, including fibroblast-to-myofibroblast transition (12). Other ILs, such as IL-17, can similarly enhance the expression of pro-inflammatory cytokines, thereby inducing IPF and exacerbating fibrotic remodeling (13). From a diagnostic perspective, elevated expression of IL-17, IL-22, and IL-23 has been observed in lung cancer-associated IPF and is closely correlated with tumor differentiation and metastatic potential, providing valuable reference information for disease discrimination as well as targeted prevention and treatment strategies (14). In the therapeutic context, ILs have increasingly been adopted as indicators for evaluating treatment responses in IPF, and several ILs have emerged as key molecular targets. For example, a Mendelian randomization analysis by Liu and colleagues revealed that higher plasma levels of IL-7 are linked to a reduced risk of IPF, a finding that has expedited the identification of potential therapeutic targets for this disease (15). Despite the expanding literature on IPF and ILs, most studies remain confined to a limited number of ILs, and a comprehensive, systematic synthesis of this research landscape is still lacking. Recent advances in spatial and molecular studies have shown that IPF is a highly heterogeneous disease. It is not simply a uniform fibrotic process throughout the lung. Instead, fibrotic changes may occur in specific lesion areas, where epithelial injury, fibroblast activation, immune signals, and local cytokines interact with each other. This change in understanding also affects how IL-related studies should be interpreted. The key question is not only whether a certain IL is increased, but also whether specific IL-related signals are associated with disease stage, tissue context, patient stratification, or treatment response. Therefore, it is necessary to systematically organize the existing literature on IPF and ILs and to clarify how the research focus in this field has changed over time.

Bibliometrics provides a systematic and quantitative approach for analyzing research trends and hotspots within a given field (16). By examining contributions across countries, institutions, and journals, bibliometric analysis enables the integration of fragmented information into a coherent knowledge structure (17). As such, bibliometrics represents a powerful tool for synthesizing research on IPF and ILs. The present study therefore aims to comprehensively map the research landscape of IPF and ILs from 1999 to 2025 using multiple visualization tools, with the goal of delineating the academic structure, research priorities, and evolutionary trajectories of this field. Through this approach, we seek to provide new conceptual support and research directions for understanding IPF pathogenesis and its therapeutic interventions. We present this article in accordance with the BIBLIO reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0922/rc).

Methods

Data sources and search methods

This study retrieved bibliographic data from the Science Citation Index Expanded (SCI-E) of the Web of Science Core Collection (WOSCC). As one of the most widely used academic databases, WOSCC provides high authority and broad coverage and has been extensively applied in bibliometric analyses (18,19). A topic-based search strategy was adopted using the following query: (TS=(“Idiopathic Pulmonary Fibrosis” OR “IPF” OR “Familial Idiopathic Pulmonary Fibrosis” OR “Cryptogenic Fibrosing Alveolitis” OR “Usual Interstitial Pneumonia”)) AND TS=(interleukin* OR IL). The inclusion criteria required that documents be peer-reviewed articles or reviews published in English. In addition, to further characterize the clinical research landscape in this field, 15 relevant clinical studies were retrieved from PubMed. To address potential bias introduced by database updates, all data were collected on September 24, 2025. A comprehensive breakdown of the data screening process is presented in Figure 1.

Figure 1 Flowchart of data screening for IPF and interleukin-related studies. IPF, idiopathic pulmonary fibrosis; SCI-E, Science Citation Index Expanded; WOSCC, Web of Science Core Collection.

Data extraction and cleaning

All eligible bibliographic records were downloaded in plain text (.txt) format. The downloaded files were uniformly named as “download_xxx” and imported into CiteSpace for preliminary deduplication and data cleaning. Therefore, to ensure data accuracy and relevance, manual screening was undertaken: two investigators (J.X., S.C.) conducted independent screening of titles and abstracts for the exclusion of irrelevant publications. Any disagreements were adjudicated by a third investigator (L.L.) to reach final resolution. In parallel, records retrieved from PubMed underwent the same screening procedure. Following this screening, 847 records (including 15 clinical studies from PubMed) met the criteria for inclusion in the analysis.

Data analysis

CiteSpace is a Java-based visualization software designed to facilitate understanding of disciplinary evolution and research frontiers through bibliometric analysis (20,21). VOSviewer places particular emphasis on the graphical presentation of bibliometric maps and allows detailed inspection of network structures (22). In this study, CiteSpace was used to construct collaboration networks of research institutions, perform co-citation analyses of references, and implement clustering analyses of keywords and cited literature, as well as citation burst detection to recognize emerging research developments in the IL-IPF field.

VOSviewer was applied to generate keyword co-occurrence networks, and SCImago Graphica was further employed to visualize patterns of collaboration among countries and regions (23). In addition, the R package bibliometrix, a widely used bibliometric analysis tool, was employed to pinpoint core journals and calculate the average annual citation frequency per publication (24).

Results

Publication trends

A literature search of the WOSCC database retrieved 832 publications on ILs and IPF. Figure 2A illustrates the annual publication output and the cumulative publication trend over time. Overall, the volume of publications demonstrates a fluctuating but steadily increasing trajectory. In 1999, only four articles were published in this field; however, publication output increased over the subsequent decade. Although a marked decline was observed in 2012, with only nine publications, research activity intensified again over the following two decades, reflecting persistent and expanding scholarly focus on this area. The highest annual output was recorded in 2021 and 2024, with 71 publications each, representing peak periods of research activity.

Figure 2 Overview of field publications. (A) The number of publications each year and accumulated publications since 1999 on interleukins and idiopathic pulmonary fibrosis. (B) Average annual citation frequency per publication. (C) Overview of the basic characteristics of the including time span and source journals.

The average annual citation frequency per publication is shown in Figure 2B. The highest average citation rate occurred in 2008, with a mean of 14.78 citations per publication. This was followed by 2019, in which publications received an average of 9.22 citations. Notably, a pronounced decrease in average citation frequency was observed in 2025, which is likely attributable to the fact that a proportion of recently published articles have not yet accumulated citations.

Figure 2C gives an overview of the fundamental features of the included literature, such as the temporal distribution of the data and the number of source journals contributing to the dataset.

Institutions and countries analysis

More than 3,200 institutions have contributed to research on ILs and IPF (Figure 3A). The institutions with the highest publication output were the University of Michigan (n=16), Shanghai Jiao Tong University (n=11), and Nanjing Medical University (n=10). Detailed information on institutions with more than eight publications is provided in Table 1. Betweenness centrality, a key metric in CiteSpace analyses, reflects the potential of a node to act as a bridge between different research domains (25,26). As shown in Table 2, institutions with a betweenness centrality greater than 0.05 included The Alfred Hospital (0.14), the University of Michigan (0.13), and CSL Ltd. (0.08), which ranked highest by this measure.

Figure 3 Country and institution research analysis. (A) Collaboration network among research institutions in the interleukin-idiopathic pulmonary fibrosis field. (B) Geographic visualization of international research collaboration networks by country. (C) Country co-occurrence network based on the average publication year.

IL-IPF research has involved a total of 45 countries and regions worldwide. Countries with more than four publications were selected and displayed as the largest connected subnetwork, resulting in the inclusion of 29 countries. International collaboration patterns and geographic distributions were visualized using SCImago Graphica (Figure 3B). For publication productivity, China was the leading country (n=245, 29.45%), trailed by the United States (n=225, 27.04%) and Japan (n=94, 11.30%) in the second and third positions. China and the United States alone accounted for more than 200 publications apiece, highlighting substantial disparities in research output across countries (Table 3).

Figure 3C depicts the country collaboration network over time based on average publication year. Notably, China shows close collaborative links with the United States, Japan, Germany, and the United Kingdom. Overall, research on ILs and IPF has been predominantly concentrated in developed countries. Nodes representing China, India, and Egypt appear in yellow, indicating that these countries have emerged more recently as active contributors to this field. In Table 4, the United States recorded 19,214 citations, nearly three times as many as China (n=6,480).

Journals analysis

To examine the distribution of journals within the IL-IPF research field, bibliometric analysis was performed using the R package bibliometrix. Figure 4A shows the 10 most productive journals in terms of publication count, each of which published more than 15 articles related to ILs and IPF. The top three of these were American Journal of Physiology-Lung Cellular and Molecular Physiology (n=28, IF =3.5), American Journal of Respiratory Cell and Molecular Biology (n=27, IF =5.3), and Frontiers in Immunology (n=26, IF =5.9).

Figure 4 Journal analysis. (A) The top 10 journals for papers around interleukins and idiopathic pulmonary fibrosis. (B) Core journals were determined using Bradford’s law.

Among the 10 journals that have made substantial contributions to IL-IPF research (Table 5), the greatest impact factor can be found in the European Respiratory Journal (IF =21.2), followed by the American Journal of Respiratory and Critical Care Medicine with an impact factor of 19.4 in 2024. Bradford’s law, one of the three classical laws in bibliometrics, is widely used to identify core journals within a research field (27). By ranking journals based on the quantity of papers they publish, these journals can be divided into three zones: core, related, and peripheral. Journals located in Zone 1 are considered core journals for the field; in the present analysis, 15 journals were classified into this core zone, as illustrated in Figure 4B.

Co-citation analysis

A study field’s intellectual foundation is greatly influenced by highly co-cited articles. Table 6 summarizes the top 10 references with the highest co-citation frequencies. The most frequently co-cited publication was “An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-Based Guidelines for Diagnosis and Management” by Raghu et al. (n=40).

A co-citation clustering network of references was further constructed (Figure 5A), which reflects the thematic evolution of IL-IPF research across different periods. The largest cluster, labeled #0 “bleomycin injury”, comprised 58 references. In contrast, the most recent cluster, #13 “design synthesis”, included 16 references and exhibited the most recent mean publication year [2022], indicating that this topic has emerged as a developing research focus.

Figure 5 Co-citation analysis of reference. (A) Reference co-citation network and clustering analysis in interleukin-idiopathic pulmonary fibrosis research. (B) Top 25 References by Citation Burst Strength.

References exhibiting strong citation bursts are considered indicative of major research trends during specific time periods (28). In the present study, the top 25 references with the highest burst strength were selected for analysis and ranked according to the onset time of citation bursts (Figure 5B). The strongest citation burst (21.63) emerged in 2011: “An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-Based Guidelines for Diagnosis and Management” (29). Its concurrent ranking as the most highly co-cited reference further underscores its foundational role in IL-IPF research.

“Inflammation and Immunity in IPF Pathogenesis and Treatment” emerged as the reference with the longest citation burst span, spanning 2020 to 2025. This review systematically delineates the roles of diverse immune cell populations in IPF progression, summarizes the effects of antifibrotic agents such as pirfenidone and nintedanib on inflammatory processes, and discusses potential reasons for the failure of inflammation-targeted clinical trials over recent decades, thereby providing important insights for subsequent therapeutic strategies in IPF (30).

Keywords analysis

Keywords often denote the dominant hotspots and new frontiers of a specific field. For the sake of analytical accuracy, keyword preprocessing was performed prior to visualization. Variants arising from singular and plural forms, abbreviations, and full terms were merged, such as “adhesion molecule” and “adhesion molecules”, as well as “interleukin 13” and “IL-13.” Figure 6A presents the keyword density visualization, with inclusion restricted to keywords that occurred at least 10 times. The five most frequent keywords were IPF (n=490), expression (n=251), inflammation (n=218), pulmonary fibrosis (n=171), and activation (n=123). The prominence of additional high-frequency keywords, including cytokines and bleomycin, indicates that elucidation of IPF pathogenesis and the development of novel therapeutic approaches remain central research directions.

Figure 6 Keywords analysis. (A) Keyword co-occurrence network and clustering analysis in interleukin-idiopathic pulmonary fibrosis research. (B) Average publication year-based keyword timeline visualization. (C) The top 25 keywords of strongest citation burst intensity.

Based on the average publication year, the keyword overlay visualization provides a clearer depiction of shifting research foci over time (Figure 6B). Keywords positioned closer to yellow represent earlier average appearance times, whereas nodes colored toward red indicate more recent emergence. Notably, keywords such as biomarkers, IL-33, and IL-11 appear in red, suggesting that these topics represent current or emerging research directions. Table 7 presents the specific clustering information. Network modularity (Q value) and silhouette score (S value) are key parameters for evaluating the quality of CiteSpace-generated clusters (31). A Q value exceeding 0.3 denotes a significant and well-structured clustering network, while an S value exceeding 0.7 reflects high cluster reliability (32). The clustering analysis in this study produced a Q-value of 0.6769 (>0.3) and an S-value of 0.8707 (>0.7), indicating robust and credible clustering performance. In total, the keywords were grouped into 14 clusters, ranked according to cluster size, with cluster #0 representing the largest group, followed by cluster #1, and so forth. Among these, cluster #10 emerged as the most recent cluster, with a mean publication year of 2021, highlighting its relevance to current research activity.

The chronological evolution of research topics can be comprehensively demonstrated through the keyword timeline display (Figure 6B). Early studies on IPF and ILs primarily focused on interstitial lung disease and pulmonary fibrosis itself, with activated T cells and transforming growth factor-β (TGF-β) constituting key mechanistic targets. Keywords within cluster #7 (gene expression) appeared relatively early, indicating an early emphasis on genetic and transcriptional perspectives to elucidate IPF pathogenesis. Although many keywords gained attention during early stages, they have remained active topics of discussion over time. In contrast, previously underexplored clusters, such as cluster #10 (nintedanib) and cluster #13 (senescence), have gained increasing attention in recent years, suggesting their emergence as novel research directions.

Burst detection analysis was further applied to identify keywords exhibiting sudden increases in usage over specific time periods (Figure 6C). mice showed the highest burst intensity (11.17), spanning from 2015 to 2018. In contrast, messenger RNA exhibited the longest burst duration, extending from 2000 to 2013. Notably, pirfenidone, diagnosis, and fibrosis displayed sustained burst activity through 2024, suggesting these keywords will remain prominent topics in current and near-future research.

PubMed clinical study analysis

PubMed hosts a large collection of biomedical literature and serves as a key information source for scientific research (33). To further characterize the clinical research landscape of IPF and ILs, fifteen clinical studies published between 1995 and 2025 were incorporated into the analysis. Figure 7 presents a keyword overlay visualization generated using VOSviewer, in which nodes representing earlier time points are shown in purple.

Figure 7 PubMed clinical trial research keyword co-occurrence map.

Between 1995 and 2002, research in this field primarily focused on IPF from cellular and biomolecular perspectives. Representative early keywords included bronchoalveolar lavage fluid, collagen disease, and IL-8. Bronchoalveolar lavage fluid has played an important role in IPF research, as it allows investigators to assess baseline biological conditions and has served as a foundation for IPF diagnosis as well as for the identification of biochemical changes relevant to the development of novel therapeutic agents.

From 2003 to 2007, studies on IPF and ILs gradually shifted toward an immunological focus. During this period, keywords such as immunoglobulin G, cytokines, and alveolar macrophages appeared for the first time. Between 2008 and 2012, terms including human, male, and aged occurred with increasing frequency, indicating that older individuals—particularly males—were the predominant populations studied. This pattern aligns with the epidemiological features of IPF, a condition that primarily affects individuals over 65 years of age and has a higher male incidence (34).

During the period from 2013 to 2017, multiple IL receptors, including IL-4 receptor alpha, IL-13 receptor alpha 2, IL-13 receptor alpha 1, and IL-6 receptor, were identified, highlighting their potential relevance to advances in IPF research. In the most recent period, from 2018 to 2025, nodes corresponding to keywords such as biomarkers and IL-13 appeared in red, reflecting their high occurrence frequency and widespread discussion during this time frame.

Discussion

Overview and key topics

In the present study, 832 publications indexed in the WOSCC from 1999 to 2025, together with 15 clinical studies retrieved from PubMed, were incorporated into a systematic analysis in order to delineate the knowledge structure, research hotspots, and developmental tendencies of IL-related research in IPF. Overall, the research focus in this field appears to have undergone a gradual but recognizable shift. Earlier studies were more frequently centered on inflammation-associated phenomena and corresponding expression changes, whereas more recent investigations have increasingly moved toward issues related to diagnosis, measurable biomarkers, and antifibrotic therapeutic contexts, as also reflected in Figures 2,6,7. This transition indicates an increasing focus on the potential role of these indicators in patient stratification and treatment response evaluation. However, these bibliometric findings should be understood as evidence of changing research attention rather than direct proof of causal relationships between specific IL pathways and IPF progression or treatment response.

Existing studies also suggest that precision medicine research in pulmonary fibrosis is moving in a similar direction. For example, clustering analyses based on circulating biomarkers may help identify distinct molecular characteristics among different patient groups, and such differences may, to some extent, be related to the heterogeneity of clinical outcomes (35,36). At the same time, prognosis and treatment response in IPF and other fibrotic interstitial lung diseases are also influenced by multiple clinical and treatment-related factors, including disease behavior, radiological progression, comorbidities, timing of antifibrotic initiation, drug tolerability, treatment adherence, and long-term management strategies (37,38). Therefore, the present bibliometric results, when considered together with existing clinical evidence, support the scientific value of continued biomarker- and stratification-oriented research in IL-related IPF studies. Nevertheless, these findings should be interpreted cautiously. They indicate a meaningful and evidence-supported research direction, but they do not demonstrate that a stable, clinically validated, and directly applicable IL-based classification system has already been established.

Bibliometric evolution and research focus of IL-related signals

Based on the keyword clustering results and the temporal evolution of the field, research on IPF and ILs appears to have shown several overlapping phases of thematic development. In the early stage, studies mainly relied on experimental models and expression profiling, with major attention being given to changes in disease-related molecules. In the middle stage, the research focus gradually turned toward immune mechanisms and canonical fibrotic pathways. In more recent years, studies have placed greater emphasis on interpretation and application in clinical contexts, with increasing attention being directed to the relationships of these signals with diagnosis, stratification, and treatment. This trend can be observed more clearly in the keyword evolution and clustering results (Figure 6, Table 7).

From a bibliometric perspective, this change suggests an expansion of research attention. Earlier studies were more often concerned with whether a certain IL was elevated and whether it was associated with inflammation or fibrosis. With the gradual accumulation of evidence, simple descriptions of expression changes have become less sufficient for explaining the differences observed among patients with IPF, and they are also less able to explain why similar molecular abnormalities do not necessarily correspond to the same disease course or treatment response. Therefore, more recent studies have increasingly attempted to further examine whether these signals may play more important roles at specific disease stages, in specific tissue regions, and within specific patterns of cellular interaction. In other words, the research focus seems to be shifting from the mere description of correlations toward a more contextual discussion of IL-related signals in different pathological settings.

Spatial transcriptomic studies have suggested that fibrotic lesions in human IPF lung tissue and related experimental models may not be distributed in a uniform manner, but may instead show a pattern in which disease activity is more concentrated in certain local regions (39). Within these regions, abnormal epithelial cells, fibroblasts, and the surrounding signaling environment may form persistent interactions, and TGF-β-related signaling has been considered likely to participate in this process (39). From this perspective, the biological meaning represented by the same IL may not be entirely identical across different locations, different stages, or even different contexts of cell-to-cell communication. In this study, such spatial evidence is used only to contextualize recent research interests identified by bibliometric analysis.

Accordingly, the implication of this stage of research is that the interpretation of IL-related signals should not be separated from the specific pathological background. In future studies, in addition to paying attention to molecular-level changes, it may also be necessary to consider the spatial location of these signals, the disease stages they may correspond to, and their links with other cellular signals, so as to further evaluate their possible clinical and biological relevance in IPF. For the bibliometric results of the present study, this may also help explain why the recent research hotspots have gradually moved toward biomarkers, stratification, and treatment evaluation (Figure 6, Table 7).

Possible reasons for the limited efficacy of broad anti-inflammatory strategies

Based on the co-citation network and citation burst results, clinical diagnostic frameworks and highly influential reviews occupy a relatively important position in this field (Figure 5, Table 6). This suggests that the focus of research on IPF and ILs is no longer limited to whether inflammation is involved in disease development. Instead, greater attention is now being given to how immune responses function in different patients, at different disease stages, and under different pathological conditions.

Against this background, the fact that some broad anti-inflammatory strategies have not achieved stable effects in IPF does not necessarily mean that immune pathways are unimportant. One possible explanation is that current research and intervention strategies may still have limitations in patient stratification, timing of intervention, and judgment of disease context. For example, if the molecular characteristics of different patients are not distinguished, signals that may be more relevant in a specific subgroup can be diluted in the overall results. If treatment is given after a more suitable stage has already passed, it may be difficult to obtain an ideal response even when the relevant pathway is still present. In addition, changes in peripheral blood markers may not fully reflect the local state of cell communication in lung tissue. Therefore, there are also limitations in inferring intrapulmonary pathological processes only from peripheral signals.

Accordingly, the limited efficacy of broad anti-inflammatory strategies should not be simply understood as evidence that anti-inflammatory approaches are ineffective. Rather, it may indicate that current studies have not yet fully clarified which patients are more suitable for intervention, when intervention is more appropriate, and how peripheral indicators correspond to local tissue changes. On this basis, the interpretation of IL-related signals should not remain at the level of a simple pro-inflammatory or anti-inflammatory distinction. Instead, future studies should further analyze their roles in specific contexts by taking patient stratification, disease stage, and the local pathological environment into account.

Potential patient grouping based on IL-related signaling and circulating biomarkers

From the perspective of translational research, patients with IPF may not be regarded as a completely homogeneous population. Different patients may show a certain degree of variation in IL-related signaling as well as in the levels of other circulating biomarkers. On the basis of these differences, identifying distinct patient subgroups may represent a research direction worthy of further attention. In this bibliometric study, patient grouping is discussed as a possible future research direction rather than as an established clinical classification model. Here, patient grouping refers to exploratory biological stratification using detectable indicators, rather than simple severity-based classification.

A similar logic has been applied in infectious, systemic inflammatory, and airway diseases, where cytokine- or chemokine-related patterns have been used to describe biologically distinct patient groups and guide targeted treatment directions (40,41). These findings do not mean that IPF can directly adopt the same model, but they provide a conceptual reference for future subgroup analyses.

In the field of IPF, some studies have already attempted to carry out related analyses around circulating biomarkers. The INMARK-related studies included markers of extracellular matrix turnover, epithelial injury, and inflammation, such as KL-6, SP-D, CRP, and ICAM-1 (42,43). These indicators are not equivalent to ILs themselves, but they may provide clinically accessible reference indicators for exploratory subgroup research. Although the associations between several baseline biomarkers and 52-week disease progression remain unstable, treatment-associated changes in CA-125, SP-D, C3A, and C3M suggest that some circulating biomarkers may have pharmacodynamic observational value (42,43). However, these findings are still insufficient to support the establishment of a mature and stable patient grouping system, and are more appropriately understood as reference evidence for subsequent grouping research and therapeutic response evaluation.

Therefore, if this line of thinking is to be applied to IPF, a more meaningful approach may be to first screen relatively stable and reproducible IL-related indicators together with other circulating biomarkers from clinically accessible samples, and then to analyze whether these indicators can help identify different patient subgroups. At the same time, it is still necessary to further determine whether these peripheral signals have a certain degree of correspondence with local pathological processes in lung tissue, and whether different subgroups show different disease-course characteristics or treatment responses. The value of this approach would depend on whether future studies can confirm that these indicator patterns are reproducible and clinically meaningful.

IL-11-related signaling as an emerging candidate axis in aging-related fibrosis research

On the basis of the above patient grouping research, a further issue that needs to be considered is which IL-related signals have accumulated relatively sufficient evidence at the present stage and may therefore represent candidate topics for subsequent validation. In combination with changes in research hotspots and the currently available evidence, IL-11 has occupied a relatively prominent position in recent IPF-related research. The keyword clustering results show that aging has gradually become one of the important themes in this field (Figure 6, Table 7). This change suggests that researchers are increasingly trying to understand the biological basis of aging-related mechanisms associated with fibrotic progression from the perspective of the SASP and its downstream effects.

Against this background, the attention given to IL-11 is mainly related to its involvement in both aging and fibrosis. Existing reviews have proposed that IL-11 may be a component of the SASP and may participate in several profibrotic processes in the lung, including fibroblast activation and related phenotypic transition (12). On this basis, it may be inferred that IL-11-related signaling may be discussed not only in relation to inflammatory responses, but also in relation to aging-associated fibrotic processes. However, in the context of the present bibliometric study, IL-11 should be interpreted as an emerging candidate axis identified from recent research attention, rather than as a fully validated therapeutic target in IPF.

Current experimental studies provide partial support for this view. For example, inhalable siRNA nanodelivery targeting IL-11 has shown antifibrotic effects in experimental pulmonary fibrosis models (44). In addition, some studies have reported that inhibition of IL-11 signaling is associated with extension of healthspan and lifespan in mammals (45,46). However, these data still mainly come from experimental studies and related discussions. Therefore, they are more appropriately regarded as indirect evidence suggesting that IL-11 may connect aging-related processes with fibrosis, rather than as direct evidence that IL-11 is a clinically validated therapeutic target in IPF.

Accordingly, based on the current research foundation, IL-11 may be regarded as a candidate signaling axis with value for further validation. Future studies may continue to examine, with clinical samples and prospective data, whether IL-11-related indicators are associated with fibrotic activity, disease progression, or treatment-related changes. Only when these relationships receive more stable support can the significance of IL-11 in patient grouping and treatment response evaluation become clearer.

The possible significance of IL-33-related signaling during acute exacerbation

In contrast to IL-11, which has been increasingly discussed in aging-related fibrosis research, IL-33-related signaling may be more appropriately discussed in relation to stage-related disease activity, including acute exacerbation. Current studies suggest that the role of IL-33 may not lie primarily in the long-term maintenance of established fibrosis, but may be more closely related to early responses after epithelial injury, changes in the local immune environment, and short-term fluctuations in disease condition. Therefore, IL-33-related signaling may be better interpreted within the context of dynamic disease progression, rather than being simply regarded as a continuously stable profibrotic factor. This interpretation should be regarded as a hypothesis derived from existing mechanistic literature, not as a conclusion directly established by the present bibliometric analysis. Research on the IL-33/ST2 signaling axis also suggests that after fibrosis has already been established, this pathway may not be the core driver for maintaining the lesion (47). This finding supports the possibility that IL-33 may have a stage-dependent role, and its significance may be more likely to appear in the amplification of alarm-like signaling after epithelial injury, and in the regulation of local immune responses during acute events or repeated injury input, thereby participating in changes in disease status.

This view is generally consistent with some findings from studies on acute exacerbation. Review studies have pointed out that acute exacerbation of IPF is often accompanied by immune imbalance and impaired host defense (48). Under this background, signals such as IL-33, which are related to epithelial injury and immune bias, may be more likely to show significance during short-term changes in disease condition. Therefore, the research value of IL-33-related signaling may not mainly lie in explaining why long-term fibrosis continues to exist, but may be more relevant to future studies on acute exacerbation risk and potential intervention windows. However, this interpretation is still mainly based on mechanistic studies and review-level evidence. Further clinical data are still needed to determine whether changes in IL-33 levels are stably associated with the risk of acute exacerbation, short-term disease fluctuation, or specific treatment windows. Only after these relationships receive more sufficient support can the significance of IL-33 in risk assessment and stage judgment become clearer.

Existing antifibrotic therapies provide a practical setting for the observation and validation of IL-related signals

The previous two sections discussed IL-11 as an emerging candidate axis in aging-related fibrosis research and IL-33 as a stage-dependent candidate pathway. A further question is how these IL-related signals can be observed and evaluated under current treatment conditions. Keyword evolution showed that pirfenidone and nintedanib have remained important topics in this field (Figure 6). This suggests that existing antifibrotic therapies not only form the clinical background of IPF research, but also provide a practical setting for analyzing signal changes during disease progression and treatment response. Recent clinical studies also indicate that treatment outcomes in IPF and progressive fibrotic interstitial lung diseases are influenced by treatment-related variables, including timing of antifibrotic initiation, tolerability, adherence, dose adjustment, and longitudinal management strategies (37,38). If certain signals change before and after treatment and are related to disease activity, tissue injury, or therapeutic response, their research value may become clearer.

In this context, antifibrotic treatment may serve as a link between mechanistic research and clinical observation. Candidate axes such as IL-11 and IL-33 may be explored alongside indicators of fibrotic activity, disease fluctuation, and treatment-related changes. However, such findings still mainly suggest associations and are not sufficient for stable prediction of treatment efficacy. In addition, a Mendelian randomization study based on druggable genes suggested that IL-7 may be a candidate therapeutic target in IPF that warrants further validation (15). Although this kind of evidence cannot replace mechanistic or clinical studies, it may help identify IL-related pathways that deserve further investigation.

Key priorities for future validation

Based on the findings of the present study, future work may further focus on the clinical validation of IL-related signals. The more important directions include whether detectable peripheral indicators can reflect local pathological changes in lung tissue with relative stability, whether different signaling patterns correspond to different disease-course features, and whether these differences are related to treatment response. Because bibliometric analysis can identify research trends but cannot validate biomarker performance or therapeutic predictive value, these questions need to be addressed through clinical samples, repeated measurements, and prospective follow-up data.

In terms of study design, future research may place peripheral blood indicators, pathological features of lung tissue, and dynamic changes during treatment within the same analytical framework as much as possible. To avoid interpreting IL-related signals in isolation, future studies should also incorporate key clinical and treatment-related variables when evaluating their stratification or predictive value. Where conditions permit, spatial omics approaches may also be incorporated to further analyze the correspondence between peripheral signals and local lesion areas. This may help move current research from correlation-based observation toward clinical validation, and it is also consistent with the recent shift of research attention toward biomarkers, patient grouping, and treatment evaluation, as also reflected in Figures 6,7.

Limitations

The limitations of this study are inherent to bibliometric analyses, including database and language bias, citation lag, terminology heterogeneity, and potential errors arising from synonym merging. Importantly, identified hotspots and clusters serve primarily to generate hypotheses rather than to establish causal mechanisms (Figures 2,7). We therefore propose that this work be positioned as a priority map to inform subsequent mechanistic experiments, cohort studies, and stratified clinical trials, providing candidate IL modules and validation pathways for future investigation.

Conclusions

By integrating 832 publications indexed in the WOSCC between 1999 and 2025 with 15 clinical studies retrieved from PubMed, this study constructs a structured knowledge map of the IL-IPF research landscape, systematically outlining research output, collaboration networks, intellectual foundations, and thematic evolution. Collectively, the field appears to be undergoing a gradual shift in research attention from early emphasis on mechanistic signals and expression profiling toward greater interest in diagnostic stratification, quantifiable biomarkers, and antifibrotic treatment context. This convergence is reflected in both keyword dynamics and co-citation structures, with sustained prominence of themes such as pirfenidone, diagnosis, and fibrosis, alongside more recent concentration on nintedanib, senescence, biomarkers, and IL-11- and IL-33-associated signaling axes.

On this basis, we propose a bibliometric framework for future validation and translational research that uses IL-driven communication features as stratification cues. This approach advances research questions from whether a given IL is elevated to whether a specific IL axis shows stage-specific or context-dependent relevance within defined disease stages, tissue compartments, and cellular interaction architectures, with treatment response evaluation serving as an important direction for future validation. Such a framework may help explain why broad anti-inflammatory strategies have not produced consistent clinical benefits and provides a clearer, testable roadmap for future studies: localizing IL modules within spatial niches, validating stratification–outcome associations in prospective and real-world datasets, and using existing antifibrotic treatment settings to observe treatment-related signal changes. Importantly, bibliometric analysis captures shifts in knowledge structure and research attention but does not equate to causal inference. Accordingly, this work should be viewed as a priority map and research design guide, intended to identify IL axes and key questions most worthy of mechanistic validation and stratified clinical testing. Overall, the present study provides structured support for advancing IL-IPF research from hotspot aggregation toward more cautious, clinically validated, and mechanistically testable research directions.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the BIBLIO reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0922/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0922/prf

Funding: This work was supported by the Jiangsu Provincial Fund for Traditional Chinese Medicine and Integrated Traditional Chinese and Western Medicine Scientific Research Projects (Revitalization and Development Program) (grant No. ZXFZ2026061), and the Natural Science Foundation of Nanjing University of Chinese Medicine (grant No. XZR2024364).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0922/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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