A Bibliometric Analysis of Oxidative Stress Research in Liver Cirrhosis: Trends, Hotspots, and Future Directions

A Bibliometric Analysis of Oxidative Stress Research in Liver Cirrhosis: Trends, Hotspots, and Future Directions | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Bibliometric Analysis of Oxidative Stress Research in Liver Cirrhosis: Trends, Hotspots, and Future Directions Kristina Baktikulova, Saulesh Kurmangaliyeva, Kairat Kurmangaliev, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5648355/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Oxidative stress is a critical factor in the pathophysiology of liver diseases, including chronic conditions and cirrhosis. However, the scientific landscape in this field remains fragmented. This bibliometric analysis aims to systematize existing research, identify major trends, and outline emerging directions. Data from the Scopus and Web of Science databases were analyzed, with a focus on peer-reviewed publications from 1991 to 2023. The key metrics included publication counts, citation analysis, keyword co-occurrence, and thematic mapping. The results revealed substantial growth in publications on oxidative stress and liver diseases over the past two decades. Key research areas include liver fibrosis, alcohol-induced liver damage, nonalcoholic fatty liver disease (NAFLD), and the therapeutic potential of antioxidants. The United States leads research output, demonstrating active collaboration with the United Kingdom, Germany, China, and Saudi Arabia. Emerging contributors, such as India, Egypt, and Brazil, are also gaining prominence, albeit on a smaller scale. Keyword analysis identified new areas of focus, such as "mitochondrial dysfunction," "antioxidant therapy," and "redox signaling." Coauthorship networks highlight the global nature of research, with an increasing trend toward international collaboration. These findings emphasize the need to develop targeted antioxidant therapies, integrate oxidative stress biomarkers into clinical practice, and advance precision medicine approaches. This analysis offers valuable insights into the trajectory of oxidative stress research in liver diseases, providing a foundation for future investigations and clinical applications. Immunology Critical Care & Emergency Medicine Gastroenterology & Hepatology eryptosis antioxidant therapy liver fibrosis collaboration networks bibliometric analysis oxidative biomarkers Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. Introduction Cirrhosis is a leading cause of mortality and morbidity worldwide. In 2016, it was the 11th leading cause of death and the 15th leading cause of morbidity, accounting for 2.2% of deaths and 1.5% of disability-adjusted life years globally ( 1 ). Liver cirrhosis represents the devastating terminal stage of various chronic liver diseases (CLDs), with fibrosis as its precursor. Risk factors such as obesity, hyperlipidemia, and type 2 diabetes mellitus (T2DM) significantly increase the likelihood of developing liver cirrhosis and its complications. Nonalcoholic steatohepatitis (NASH), a condition characterized by excessive lipid accumulation in nonalcoholic fatty liver disease (NAFLD), leads to inflammation and hepatocyte destruction, with a 20% progression rate to cirrhosis. Both cirrhosis and liver fibrosis are multifaceted diseases involving inflammatory cytokines, genetic predispositions, oxidative stress, and endoplasmic reticulum (ER) stress. Eryptosis, the programmed death of erythrocytes, has gained significant attention due to its role in various physiological and pathological processes. Defined by cell shrinkage, membrane blebbing, and externalization of phosphatidylserine (PS), eryptosis resembles apoptosis but occurs uniquely in anucleate red blood cells. While this mechanism is crucial in maintaining homeostasis by removing defective erythrocytes, its dysregulation is increasingly associated with pathological conditions such as anemia, systemic inflammation, and oxidative stress ( 2 ). The relationship between eryptosis and liver disorders has drawn growing interest, particularly for its potential impact on disease severity and patient outcomes (Fig. 1 ). The liver, a central metabolic and hematological regulatory organ, plays a pivotal role in erythrocyte turnover and the pathological processes driving eryptosis. Chronic liver diseases—including those caused by hepatitis B (HBV) and hepatitis C (HCV) viruses, alcohol abuse, and NASH—are frequently associated with anemia, which is strongly linked to disease progression and poor prognoses ( 3 ). Anemia in these conditions is multifactorial, with heightened eryptosis driven by oxidative stress, elevated intracellular calcium levels, and systemic inflammation increasingly recognized as contributing factors ( 4 ). For example, oxidative stress in chronic liver diseases exacerbates redox imbalances, activating eryptotic pathways such as PS externalization and ion channel dysregulation ( 5 ). Elevated intracellular calcium levels further promote the activation of caspases and calpains, which are key mediators of eryptosis ( 6 ). Emerging evidence suggests that eryptosis is not merely a consequence of liver disease but may actively contribute to its pathogenesis by exacerbating systemic inflammation, impairing oxygen delivery, and amplifying oxidative damage ( 7 ). These processes create a vicious cycle that accelerates liver damage and erythrocyte destruction. Despite these insights, significant gaps remain in understanding the molecular mechanisms linking eryptosis to liver disease progression. Notably, the diagnostic and therapeutic potential of eryptosis biomarkers—such as PS exposure, caspase activation, and intracellular calcium levels—has yet to be fully explored, presenting opportunities for research innovation. This article provides a comprehensive review of current trends in eryptosis research, focusing on its role in liver diseases. It aims to elucidate the mechanisms underlying eryptosis in hepatic pathologies, highlight its emerging potential as a diagnostic and therapeutic target, and propose future directions for integrating eryptosis biomarkers into clinical practice. By enhancing our understanding of eryptosis, this research seeks to pave the way for biomarker-driven approaches to diagnosing and treating liver diseases, ultimately improving patient outcomes. Additionally, other cell death mechanisms related to oxidative damage, such as necroptosis, ferroptosis, and pyroptosis, have been implicated in liver diseases and systemic inflammation, as demonstrated in studies on chromium-induced toxicity ( 8 ). 2. Materials and Methods 2.1. Bibliometric analysis To perform a comprehensive bibliometric review of studies on "eryptosis" in the context of "liver cirrhosis," we retrieved data from the Web of Science Core Collection (WOS-CC) and Scopus databases. Our research strategy was designed to encompass a broad spectrum of aspects related to this topic. Data collection was completed in November 2024. 2.2. Search strategy The search protocol was designed to identify relevant studies on oxidative stress in patients with liver cirrhosis. Specifically, the term "oxidative stress" was searched within the title field, while the combination of "oxidative stress" and "liver cirrhosis" was searched within the abstract field (Table 1 ). Based on the indexing capabilities of the Web of Science and Scopus databases, the search focused on publications from 1991 to 2024, with no additional time restrictions applied. 2.3. Inclusion and Exclusion Criteria Inclusion Criteria: Original research articles and review papers published in English that directly addressed oxidative stress in patients with liver cirrhosis were included. Exclusion Criteria: Non-research publications (e.g., conference abstracts, editorials, book chapters) and studies that did not explicitly address oxidative stress in patients with liver cirrhosis were excluded. The article selection process is illustrated in Fig. 2 . Table 1 Queries are used to extract data from Scopus and Web of Science databases (author keywords OR title OR abstract) for a bibliometric analysis of oxidative stress research in liver cirrhosis Code Queries Number of articles Scopus Web of Science #1 "Oxidative Stresses" OR "Stress, Oxidative" OR "Oxidative Damage" OR "Damage, Oxidative" OR "Oxidative Damages" OR "Oxidative Injury" OR "Injury, Oxidative" OR "Oxidative Injuries" OR "Oxidative Stress Injury" OR "Injury, Oxidative Stress" OR "Oxidative Stress Injuries" OR "Stress Injury, Oxidative" OR "Oxidative Cleavage" OR "Cleavage, Oxidative" OR "Oxidative Cleavages" OR "Antioxidative Stress" OR "Antioxidative Stresses" OR "Stress, Antioxidative" OR "Antioxidative Stress" OR "Antioxidative Stress" OR "Antioxidative Stresses" OR "Stress, Antioxidative" 525523 66223 #2 "Liver Cirrhosis" 419339 252702 #3 #1 AND #2 354 285 2.4. RStudio and Biblioshiny analyses The bibliometric analysis was conducted using RStudio (version 4.4.2), an open-source statistical software platform, in combination with the Bibliometrix R package, a widely used tool for comprehensive bibliometric studies ( 9 ). The analysis, finalized on 17 November 2024, also utilized Biblioshiny, an interactive web-based application integrated with Bibliometrix, to simplify and enhance bibliometric exploration. For improved visualization, charts depicting annual scientific output and average citations per year, originally generated in Biblioshiny, were recreated using Flourish Studio ( https://flourish.studio/ ). At this stage of the research, original articles were selected through a two-step process conducted by S.K. and K.B. The selection criteria involved evaluating article titles and abstracts identified via a systematic search strategy. Articles approved by both authors were then subjected to full-text analysis. In cases of disagreement, the final decision was made by a third author, K.K. 2.5. Outline of key institutions, influential publications, leading authors, and associated nations We developed visual representations to highlight the relationships between the most influential institutions and authors, providing insights into their collaborative efforts. Countries were assessed based on their academic output, represented by the proportion of publications each contributed. Furthermore, we analyzed the level of collaboration among the top 10 most productive nations. To visually represent this cooperation, a map was created to depict the number of publications produced by each country. 2.6. Analysis of keyword frequency A detailed chronological analysis was performed to track the periodic emergence of key terms over time. A TreeMap was created to visually represent the distribution and prominence of the top 10 most frequently occurring keywords. Furthermore, a comprehensive thematic analysis was conducted to identify dominant trends and recurring themes within the selected articles (Fig. 4 ). 3. Results 3.1 Comprehensive overview of the manuscripts The study analyzed 627 documents from 358 sources published between 1991 and 2024. The analysis included 6,942 keywords and 1,699 author-provided keywords, reflecting a broad thematic scope and the richness of the research landscape. A total of 3,791 authors contributed to the publications, with only seven documents authored by a single individual, underscoring the highly collaborative nature of this field. On average, each document involved 8.45 coauthors, highlighting the extensive teamwork characteristic of this research domain. However, international collaboration was observed in only 4.85% of the documents, indicating that most studies were conducted within national or institutional boundaries. The most cited document, authored by Okuda et al., focused on mitochondrial injury and oxidative stress induced by the hepatitis C virus, garnering an impressive 756 citations and published in Gastroenterology. Recent works, such as those by Zhang et al. (2023) and Xiao et al. (2023), highlight cutting-edge therapeutic approaches involving stem cell-derived exosomes and epigenetic regulation of inflammasomes. Table 2 provides an overview of the top 10 most cited publications on the relationship between oxidative stress and liver cirrhosis. Table 2 Top 10 most cited publications on the relationship between oxidative stress and liver cirrhosis (1991–2024) Rank Authors (References) Title of the document Journal name Total citations DOI 1 Okuda et al. ( 10 ) Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein Gastroenterology 756 10.1053/gast.2002.30983 2 Sanyal et al. ( 11 ) A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis New Engl J Med 28 10.1053/gast.2002.30983 3 Häussinger et al. ( 12 ) Hepatic encephalopathy Nat Rev Disease Prim 82 10.1053/gast.2002.30983 4 Zhang et al.( 13 ) Exosomes derived from human adipose mesenchymal stem cells ameliorate hepatic fibrosis by inhibiting PI3K/Akt/mTOR pathway and remodeling choline metabolism Nanobiotechnology 45 10.1186/s12951-023-01788-4 5 Harrison et al. ( 14 ) Safety and efficacy of once-weekly efruxifermin versus placebo in nonalcoholic steatohepatitis (HARMONY): a multicenter, randomized, double-blind, placebo-controlled, phase 2b trial Lancet Gastroenterol Hepatol 42 10.1016/S2468-1253(23)00272-8 6 Xiao et al. ( 15 ) STING mediates hepatocyte pyroptosis in liver fibrosis by Epigenetically activating the NLRP3 inflammasome Redox Biol 40 10.1016/j.redox.2023.102691 7 Gane et al. ( 16 ) The mitochondrion-targeted antioxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients Liver Int 294 10.1111/j.1478-3231.2010.02250.x 8 Chen et al. ( 17 ) Deep whole-genome analysis of 494 hepatocellular carcinomas Nature 18 10.1038/s41586-024-07054-3 9 Drummer et al.( 18 ) Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages Front Immunol 31 10.3389/fimmu.2023.1113883 10 De et al. ( 19 ) Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage Hepatology 362 10.1053/he.2000.5789 3.2. Annual analysis of publications The analysis of published articles from 1991 to 2024, as illustrated in Fig. 2 , reveals a gradual upward trend in research output. Between 1991 and 2021, the number of published articles remained relatively low, fluctuating below 10 articles per year. A steady increase began in 2005, with periodic minor fluctuations. A significant surge was observed in 2022, with 30 articles published. This upward trajectory continued in 2023 and 2024, with the number of publications rising sharply to 227 and 237 articles, respectively. This remarkable growth, depicted in Fig. 2 , highlights the sustained and growing interest in oxidative stress and liver cirrhosis research. 3.3. Countries and affiliations Figure 3 A highlights the top 20 countries by the number of published articles. China leads with over 200 publications, accounting for 31.3% of the total output. However, the United Kingdom stands out as a key hub for collaboration, forming strong research partnerships with countries such as Germany, Italy, and other European nations, as illustrated in Fig. 3 B. This underscores the UK's significant role in global research networks. European countries dominate the collaboration network, showcasing dense interconnections that emphasize the strength of intra-continental cooperation. North America: The United States and Canada play prominent roles, actively fostering global research partnerships. Asia and Oceania: Countries in these regions, including India, Saudi Arabia, and New Zealand, are increasingly contributing to international research efforts, reflecting their growing presence in global collaboration networks. 3.4. Evolution of publication and citation metrics The evolution of publication and citation metrics in the field of oxidative stress and liver cirrhosis research from 1991 to 2024 reflects the growing scholarly interest and recognition of this topic. A detailed analysis reveals significant trends in the annual growth rate of publications. The annual growth rate for publications in this field is calculated at 22.08%, indicating a consistent increase in research output over the decades. Publication Trends: Early research (1991–2000) primarily focused on foundational studies that identified the relationship between oxidative stress and liver diseases, particularly hepatitis and cirrhosis. From 2001 to 2024, publications sharply increased, driven by advancements in molecular biology, imaging technologies, and therapeutic strategies. Citation Impact: The average number of citations per article during the period was 51.36, signifying the strong influence of these studies on subsequent research. Landmark publications, such as those by Okuda et al. (2002), have amassed hundreds of citations, with the most-cited paper achieving 756 citations. Top Contributing Journals: Leading journals, such as Gastroenterology, Nature, and Hepatology, have been pivotal in disseminating high-impact research. These journals frequently publish groundbreaking studies that drive innovations in understanding oxidative stress mechanisms. Author Collaboration: A notable proportion of the research (24.95%) involved international collaboration, highlighting the multidisciplinary and global nature of the field. Emerging Research Themes: In recent years, there has been a shift toward novel therapeutic approaches, including the role of exosomes, antioxidants, and molecular inhibitors targeting specific pathways. 3.5. Graphical representation Figure 5 illustrates the application of Bradford's Law of Scattering to identify the most productive journals in the field of phytomedicine, likely related to oxidative stress and liver cirrhosis. Bradford's Law categorizes journals into three zones based on their contribution to the body of research: a small number of highly productive core sources and a larger number of less productive noncore sources. 3.6. Most productive authors, institutions, countries, and their collaboration network These institutions include Cairo University (18 articles), Sichuan University (16 articles), Kashan University of Medical Sciences (15 articles), Mansoura University (15 articles), University of Padua (15 articles), Chiang Mai University (14 articles), Benha University (13 articles), King Saud University (13 articles), Pusan National University (13 articles), and Zagazig University (13 articles), reflecting active global research efforts on oxidative stress and liver cirrhosis (Fig. 6 A). Among the authors, Wang Y. distinguished himself with the highest number of articles (27, 0.21%), followed by UX, who published 25 articles (Fig. 6 B). 4. Discussion The increasing body of literature on oxidative stress and liver cirrhosis over the last three decades highlights the growing recognition of the critical role oxidative stress plays in the pathophysiology of liver diseases, particularly cirrhosis. The bibliometric analysis of 627 documents published between 1994 and 2024 revealed a marked rise in scholarly interest since 2005, which can be attributed to several key advancements in molecular biology, imaging technologies, and therapeutic strategies. This trend is indicative of the expanding research efforts to explore the mechanisms of oxidative stress in liver cirrhosis and the subsequent development of potential therapeutic interventions ( 20 ). The gradual increase in publications, particularly from 2005 onward, aligns with the growing awareness of oxidative stress as a central mechanism in liver damage. The rapid rise in publications since 2022, with over 200 articles per year, underscores the significant progress in this field and reflects an intensifying focus on oxidative stress as a crucial target for both basic and applied research ( 21 ). The annual growth rate of 22.08% further emphasizes the sustained momentum in this area, showing that the field is increasingly integrated into the broader biomedical research agenda. Notably, the annual citation rate per article, averaging 51.36 citations, reflects the growing influence of the research outputs. Landmark studies, such as Okuda et al. (2002) ( 10 ) on mitochondrial injury and oxidative stress in hepatitis C virus-infected patients, have set the foundation for much of the current understanding of oxidative stress in liver diseases. The continuing relevance of these early studies is also evident from their high citation count, which remains a point of reference for newer research. The analysis of the geographical distribution of publications indicates that China leads the field, accounting for 31.3% of total publications. This can be attributed to China's significant investments in biomedical research infrastructure and the prioritization of liver disease research ( 22 ). Furthermore, the United States, the United Kingdom, and several European countries, including Germany and Italy, have played key roles in fostering international collaborations and driving innovations in the field. These nations are home to some of the most influential institutions and researchers, as reflected in their collaborative networks. The strong interconnections between European countries and their expanding collaborations with researchers from Asia and North America highlight a global research network focused on understanding the mechanisms of oxidative stress and its impact on liver cirrhosis. The relatively low rate of international collaboration (4.85%) across the documents suggests that, despite the global significance of the topic, much of the research on oxidative stress and liver cirrhosis is still conducted within national or institutional boundaries. However, the increasing trend toward collaboration observed in recent years points to a shift towards more global cooperation, which will be crucial for addressing complex challenges such as therapeutic development and diagnostic advancement. A chronological analysis of the publication trends revealed several distinct phases in the evolution of research on oxidative stress and liver cirrhosis. Early studies (1991–2000) focused on establishing the foundational understanding of oxidative stress in liver diseases, with a particular emphasis on its role in liver fibrosis and cirrhosis caused by hepatitis. From 2001 onward, research increasingly incorporated advanced molecular techniques, such as gene expression analysis, proteomics, and advanced imaging technologies, which facilitated a deeper exploration of the cellular and molecular pathways involved in oxidative stress ( 23 ). Recent studies, particularly from 2020 onwards, have shifted focus towards novel therapeutic approaches. These include the use of stem cell-derived exosomes, antioxidants, and molecular inhibitors targeting specific oxidative stress pathways ( 24 ). The recognition of exosomes, for example, as vehicles for delivering therapeutic molecules, signals a promising area for future research and therapeutic development ( 25 ). The role of epigenetic regulation, particularly concerning inflammasomes and oxidative stress, is another emerging theme that could reshape the therapeutic landscape ( 26 ). Addressing these challenges is closely tied to the technological revolution in fields such as flow cytometry and microscopy, which enable the identification of diverse factors associated with oxidative stress, as highlighted in Tkachenko A.'s detailed analysis of pathogenesis and the critical mechanisms underlying these processes ( 27 ). The institutional landscape shows that a small group of institutions, such as Cairo University and Sichuan University, have been particularly productive in contributing to the understanding of oxidative stress in liver cirrhosis. This highlights the importance of a few core research hubs in driving forward the scientific discourse. The leading authors, such as Wang Y. and UX, have made significant contributions to the field, as evidenced by their extensive publication records. These prolific researchers continue to shape the direction of the field through their collaborative efforts and contributions to key studies. An important aspect of this bibliometric analysis is the identification of the most influential journals in the field. Journals such as Gastroenterology, Hepatology, and Nature have played a pivotal role in disseminating high-impact research that shapes the field of oxidative stress and liver cirrhosis. The application of Bradford's Law of Scattering reveals a small number of highly productive core journals that consistently publish groundbreaking studies, while a larger number of journals contribute to the literature with less frequent publications. 5. Future directions and challenges As the body of literature continues to grow, several challenges remain in the research landscape. First, there is a need for greater international collaboration to address complex questions related to the pathogenesis of oxidative stress and its role in liver cirrhosis. Although some countries are actively engaged, further efforts to enhance cross-border research initiatives will be essential for advancing the field. Additionally, while much progress has been made in understanding the molecular mechanisms of oxidative stress, the development of effective diagnostic tools and therapeutic strategies remains a critical challenge. The increasing interest in novel therapeutic approaches, such as the use of antioxidants and exosomes, holds great promise. However, the need for clinical validation and large-scale trials to assess the efficacy of these strategies is paramount. Moreover, the integration of advanced technologies such as artificial intelligence and machine learning could further accelerate the identification of new therapeutic targets and biomarkers for oxidative stress in liver diseases. 6. Conclusion The bibliometric analysis of the past three decades of research on oxidative stress and liver cirrhosis underscores the growing interest and progress in understanding this complex relationship. The significant global contributions, especially from China, the United States, and European countries, reflect the collaborative nature of this research field. Emerging therapeutic approaches, such as stem-cell derived exosomes and molecular inhibitors, represent exciting avenues for future exploration. However, continued international collaboration, technological innovation, and clinical validation are crucial for translating these findings into effective treatments for patients suffering from liver cirrhosis. Declarations Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Conflicts of interest The authors declare that they have no conflicts of interest. Author Contributions Conceptualization: S.K. and K.B.; data curation: K.K., M.M. and A.M.; formal analysis: S.K. and K.B.; investigation: K.T.; methodology: K.T. and M.M..; project administration: S.K.; resources: K.B.; software: M.M. and N.A.; supervision: S.K. and K.B.; writing—original draft: K.B.; writing—review and editing: S.K., K.K., K.T., M.M., N.A. and A.M. All authors have read and agreed to the published version of the manuscript. Funding Nofundingwasreceivedforthismanuscript. Supporting Information Additional supporting information can be found online in the Supporting Information section. Tables S1 and S2 provide the search queries for relevant articles from the Scopus and Web of Science databases, respectively. Table S3 presents the R code used to merge data from the Web of Science and Scopus databases. The code imports datasets from both sources, combines them, removes duplicates, and exports the merged data into an Excel file. References Banerjee T, Sar S, Saha S, Baidya A, Sarkar A, Karmakar S et al (2023) Herbal Medicines for the Treatment of Liver Cirrhosis. In: Dhara AK, Mandal SC, editors. Role of Herbal Medicines: Management of Lifestyle Diseases [Internet]. Singapore: Springer Nature Singapore; pp. 185–209. https://doi.org/10.1007/978-981-99-7703-1_10 Lang F, Qadri SM (2012) Mechanisms and significance of eryptosis, the suicidal death of erythrocytes. Blood Purif 33(1–3):125–130 Lang E, Lang F (2015) Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death. Semin Cell Dev Biol 39:35–42 Chrostek L (2014) Liver fibrosis markers in alcoholic liver disease. World J Gastroenterol 20(25):8018 Pretorius E, Bester J, Vermeulen N, Lipinski B, Gericke GS, Kell DB (2014) Profound Morphological Changes in the Erythrocytes and Fibrin Networks of Patients with Hemochromatosis or with Hyperferritinemia, and Their Normalization by Iron Chelators and Other Agents. Arumugam TV, editor. PLoS ONE. ;9(1):e85271 Alzoubi K, Honisch S, Abed M, Lang F (2013) Triggering of Suicidal Erythrocyte Death by Penta-O-galloyl-β-d-glucose. Toxins 6(1):54–65 Lang F, Gulbins E, Lerche H, Huber SM, Kempe DS, Foller M (2008) Eryptosis, a window to systemic disease. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 22(5–6):373–380 Kurmangaliyeva S, Baktikulova K, Tkachenko V, Seitkhanova B, Shapambayev N, Rakhimzhanova F et al (2024) An Overview of Hexavalent Chromium-Induced Necroptosis, Pyroptosis, and Ferroptosis. Biol Trace Elem Res Aria M, Cuccurullo C (2017) bibliometrix: An R-tool for comprehensive science mapping analysis. J Informetr 11(4):959–975 Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM et al (2002) Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122(2):366–375 Sanyal AJ, Bedossa P, Fraessdorf M, Neff GW, Lawitz E, Bugianesi E et al (2024) A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med 391(4):311–319 Häussinger D, Dhiman RK, Felipo V, Görg B, Jalan R, Kircheis G et al (2022) Hepatic encephalopathy. Nat Rev Dis Primer 8(1):43 Zhang Z, Shang J, Yang Q, Dai Z, Liang Y, Lai C et al (2023) Exosomes derived from human adipose mesenchymal stem cells ameliorate hepatic fibrosis by inhibiting PI3K/Akt/mTOR pathway and remodeling choline metabolism. J Nanobiotechnol 21(1):29 Harrison SA, Frias JP, Neff G, Abrams GA, Lucas KJ, Sanchez W et al (2023) Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol 8(12):1080–1093 Xiao Y, Zhao C, Tai Y, Li B, Lan T, Lai E et al (2023) STING mediates hepatocyte pyroptosis in liver fibrosis by Epigenetically activating the NLRP3 inflammasome. Redox Biol 62:102691 Gane EJ, Weilert F, Orr DW, Keogh GF, Gibson M, Lockhart MM et al (2010) The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int Off J Int Assoc Study Liver 30(7):1019–1026 Chen L, Zhang C, Xue R, Liu M, Bai J, Bao J et al (2024) Deep whole-genome analysis of 494 hepatocellular carcinomas. Nature 627(8004):586–593 Drummer C, Saaoud F, Jhala NC, Cueto R, Sun Y, Xu K et al (2023) Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages. Front Immunol 14:1113883 De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F et al (2000) Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatol Baltim Md 31(4):997–1004 Li S, Hong M, Tan HY, Wang N, Feng Y (2016) Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases. Oxid Med Cell Longev 2016:4234061 Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V et al (2017) Oxidative Stress: Harms and Benefits for Human Health. Oxid Med Cell Longev 2017:8416763 Wang FS, Fan JG, Zhang Z, Gao B, Wang HY (2014) The global burden of liver disease: the major impact of China. Hepatol Baltim Md 60(6):2099–2108 Butterfield DA (2004) Proteomics: a new approach to investigate oxidative stress in Alzheimer’s disease brain. Brain Res 1000(1–2):1–7 Xia C, Dai Z, Jin Y, Chen P (2021) Emerging Antioxidant Paradigm of Mesenchymal Stem Cell-Derived Exosome Therapy. Front Endocrinol 12:727272 Rajput A, Varshney A, Bajaj R, Pokharkar V (2022) Exosomes as New Generation Vehicles for Drug Delivery: Biomedical Applications and Future Perspectives. Mol Basel Switz 27(21):7289 Zheng X, Sawalha AH (2022) The Role of Oxidative Stress in Epigenetic Changes Underlying Autoimmunity. Antioxid Redox Signal 36(7–9):423–440 Tkachenko A (2024) Apoptosis and eryptosis: similarities and differences. Apoptosis 29(3):482–502 Additional Declarations The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5648355","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":390487407,"identity":"ee48e6ba-dc1c-468d-8210-39ba87793a27","order_by":0,"name":"Kristina Baktikulova","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYBACCQYeBsYGBgkDBnYQt4LBAEgyE6ElAagFrO4M8VoYIFoY24jQItnAe/DjzB8WxgaHmY9J/JxXZ6w7I4HZ8AceLdIMfMmSGxIkzAwOs6VJ9m5jMzO7kcCcIIFHixwDj4HkgwQJG4PDPMYGvNt4bEBaDhjg12L8E6bF8O8cCYiWBLwO4zGDOozH8DFvgwHEYQfwaJFs5kuznJEmYSx5mC3xscyxBGOzMw+bDRvwaJE43nv4Zo9NnWHf8eYDB9/U1BluO558WBJfiGGLA0Z8doyCUTAKRsEoIAYAAACCRfsgfSPWAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-1806-1058","institution":"WKMU Ospanov","correspondingAuthor":true,"prefix":"","firstName":"Kristina","middleName":"","lastName":"Baktikulova","suffix":""},{"id":390487408,"identity":"2d0b9ff5-9d0d-4914-b8d5-375776c5feba","order_by":1,"name":"Saulesh Kurmangaliyeva","email":"","orcid":"https://orcid.org/0000-0002-9502-1490","institution":"WKMU Ospanov","correspondingAuthor":false,"prefix":"","firstName":"Saulesh","middleName":"","lastName":"Kurmangaliyeva","suffix":""},{"id":390487409,"identity":"746819b1-d0a3-43ff-a664-0ee816048a55","order_by":2,"name":"Kairat Kurmangaliev","email":"","orcid":"https://orcid.org/0000-0003-3579-9003","institution":"WKMU Ospanov","correspondingAuthor":false,"prefix":"","firstName":"Kairat","middleName":"","lastName":"Kurmangaliev","suffix":""},{"id":390487410,"identity":"6f96e264-f9d8-48d1-8c58-7c3bfd5f59a3","order_by":3,"name":"Mentai Makashova","email":"","orcid":"https://orcid.org/0000-0003-0486-9187","institution":"WKMU Ospanov","correspondingAuthor":false,"prefix":"","firstName":"Mentai","middleName":"","lastName":"Makashova","suffix":""},{"id":390487411,"identity":"9abdb60c-845e-44be-b876-92dba449af14","order_by":4,"name":"Konstantin Tissin","email":"","orcid":"https://orcid.org/0009-0006-7996-5439","institution":"WKMU Ospanov","correspondingAuthor":false,"prefix":"","firstName":"Konstantin","middleName":"","lastName":"Tissin","suffix":""},{"id":390487412,"identity":"576e0e65-7722-45d4-b97b-f61014eefc15","order_by":5,"name":"Akzhan Madenbayeva","email":"","orcid":"https://orcid.org/0000-0003-1334-6628","institution":"WKMU Ospanov","correspondingAuthor":false,"prefix":"","firstName":"Akzhan","middleName":"","lastName":"Madenbayeva","suffix":""}],"badges":[],"createdAt":"2024-12-15 15:56:29","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false,"coiExplicitlySet":false},"doi":"10.21203/rs.3.rs-5648355/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5648355/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71661905,"identity":"5336ec20-4286-435a-8627-f74815160915","added_by":"auto","created_at":"2024-12-17 13:52:55","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":95197,"visible":true,"origin":"","legend":"\u003cp\u003eEryptosis and Efferocytosis in Liver Cirrhosis: Mechanisms and Implications\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5648355/v1/63074912433c4398720194c4.jpg"},{"id":71659800,"identity":"e4f32540-6c8b-45b1-83ec-431373204ded","added_by":"auto","created_at":"2024-12-17 13:28:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":21006,"visible":true,"origin":"","legend":"\u003cp\u003eSearch strategy for a bibliometric analysis of oxidative stress research in liver cirrhosis\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5648355/v1/757bc1b649493da7f7c7f473.png"},{"id":71660298,"identity":"a15e61d7-58b7-4c75-a491-28f09765b731","added_by":"auto","created_at":"2024-12-17 13:36:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":251972,"visible":true,"origin":"","legend":"\u003cp\u003eKeywords trend in research articles regarding oxidative stress research in liver cirrhosis(A) TreeMap of top 10 keywords in oxidative stress and liver cirrhosis research (1991– 2024) by frequency. (B) Scatter plot of keyword trends over time\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5648355/v1/0a19525f633db02cf9482ee2.png"},{"id":71659806,"identity":"2aa01aa4-0cbe-432d-854b-80510aff39aa","added_by":"auto","created_at":"2024-12-17 13:28:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":44261,"visible":true,"origin":"","legend":"\u003cp\u003eAnnual publication trends over time regarding the relationship between oxidative stress and liver cirrhosis (1994–2024)\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5648355/v1/00f5c7efdb977da297eda46d.png"},{"id":71659808,"identity":"b6e9b74e-4833-424f-b06c-e1051433e54d","added_by":"auto","created_at":"2024-12-17 13:28:55","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":190207,"visible":true,"origin":"","legend":"\u003cp\u003eApplication of Bradford’s Law identifying 27 core journals publishing on oxidative stress and liver cirrhosis (1991–2024).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5648355/v1/4d4c36951c480c1f3cdeb5d9.png"},{"id":71660303,"identity":"c1dfd7c1-08b2-47d4-acd4-44da04f9cca3","added_by":"auto","created_at":"2024-12-17 13:36:55","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1036346,"visible":true,"origin":"","legend":"\u003cp\u003eTop 20 countries with the highest number of articles by corresponding authors (A). Global research collaboration network (B) publishing on oxidative stress and liver cirrhosis (1991–2024)\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-5648355/v1/ecbf1a4c71e1d48f724deb9b.png"},{"id":71660305,"identity":"49052a3a-1b67-46e1-be5c-80f88e5647de","added_by":"auto","created_at":"2024-12-17 13:36:55","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":143701,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Visualization of the most prolific authors, institutions, and countries contributing to the research on oxidative stress and liver cirrhosis, along with their collaborative network. (B) A timeline illustrating the scientific contributions of the 10 leading authors in the field, highlighting their publication trends and significant works from 1991 to 2024.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-5648355/v1/9bbeeda8a3e5d0abb5362816.png"},{"id":71662856,"identity":"0def16a9-dace-4974-a6e8-afd697f37713","added_by":"auto","created_at":"2024-12-17 14:00:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2112497,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5648355/v1/5dbc2fb4-4471-41e7-ad73-26b23580cf2d.pdf"},{"id":71659803,"identity":"15301838-0bc9-46f4-95fb-99be13075054","added_by":"auto","created_at":"2024-12-17 13:28:54","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":157207,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical Abstract\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"OneHealthInterdependenceBetweenHumanAnimalEnvironmentalHealth1.png","url":"https://assets-eu.researchsquare.com/files/rs-5648355/v1/4a4f3bab496c9323672b2b5c.png"},{"id":71659831,"identity":"bffc6322-d72b-42fb-b69e-1b71bf4a8133","added_by":"auto","created_at":"2024-12-17 13:28:56","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":13699,"visible":true,"origin":"","legend":"\u003cp\u003etable\u003c/p\u003e","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-5648355/v1/8f10b9445e388307c6df97a1.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eA Bibliometric Analysis of Oxidative Stress Research in Liver Cirrhosis: Trends, Hotspots, and Future Directions\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCirrhosis is a leading cause of mortality and morbidity worldwide. In 2016, it was the 11th leading cause of death and the 15th leading cause of morbidity, accounting for 2.2% of deaths and 1.5% of disability-adjusted life years globally (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Liver cirrhosis represents the devastating terminal stage of various chronic liver diseases (CLDs), with fibrosis as its precursor. Risk factors such as obesity, hyperlipidemia, and type 2 diabetes mellitus (T2DM) significantly increase the likelihood of developing liver cirrhosis and its complications. Nonalcoholic steatohepatitis (NASH), a condition characterized by excessive lipid accumulation in nonalcoholic fatty liver disease (NAFLD), leads to inflammation and hepatocyte destruction, with a 20% progression rate to cirrhosis. Both cirrhosis and liver fibrosis are multifaceted diseases involving inflammatory cytokines, genetic predispositions, oxidative stress, and endoplasmic reticulum (ER) stress.\u003c/p\u003e \u003cp\u003eEryptosis, the programmed death of erythrocytes, has gained significant attention due to its role in various physiological and pathological processes. Defined by cell shrinkage, membrane blebbing, and externalization of phosphatidylserine (PS), eryptosis resembles apoptosis but occurs uniquely in anucleate red blood cells. While this mechanism is crucial in maintaining homeostasis by removing defective erythrocytes, its dysregulation is increasingly associated with pathological conditions such as anemia, systemic inflammation, and oxidative stress (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The relationship between eryptosis and liver disorders has drawn growing interest, particularly for its potential impact on disease severity and patient outcomes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe liver, a central metabolic and hematological regulatory organ, plays a pivotal role in erythrocyte turnover and the pathological processes driving eryptosis. Chronic liver diseases\u0026mdash;including those caused by hepatitis B (HBV) and hepatitis C (HCV) viruses, alcohol abuse, and NASH\u0026mdash;are frequently associated with anemia, which is strongly linked to disease progression and poor prognoses (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Anemia in these conditions is multifactorial, with heightened eryptosis driven by oxidative stress, elevated intracellular calcium levels, and systemic inflammation increasingly recognized as contributing factors (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). For example, oxidative stress in chronic liver diseases exacerbates redox imbalances, activating eryptotic pathways such as PS externalization and ion channel dysregulation (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Elevated intracellular calcium levels further promote the activation of caspases and calpains, which are key mediators of eryptosis (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEmerging evidence suggests that eryptosis is not merely a consequence of liver disease but may actively contribute to its pathogenesis by exacerbating systemic inflammation, impairing oxygen delivery, and amplifying oxidative damage (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). These processes create a vicious cycle that accelerates liver damage and erythrocyte destruction. Despite these insights, significant gaps remain in understanding the molecular mechanisms linking eryptosis to liver disease progression. Notably, the diagnostic and therapeutic potential of eryptosis biomarkers\u0026mdash;such as PS exposure, caspase activation, and intracellular calcium levels\u0026mdash;has yet to be fully explored, presenting opportunities for research innovation.\u003c/p\u003e \u003cp\u003eThis article provides a comprehensive review of current trends in eryptosis research, focusing on its role in liver diseases. It aims to elucidate the mechanisms underlying eryptosis in hepatic pathologies, highlight its emerging potential as a diagnostic and therapeutic target, and propose future directions for integrating eryptosis biomarkers into clinical practice. By enhancing our understanding of eryptosis, this research seeks to pave the way for biomarker-driven approaches to diagnosing and treating liver diseases, ultimately improving patient outcomes. Additionally, other cell death mechanisms related to oxidative damage, such as necroptosis, ferroptosis, and pyroptosis, have been implicated in liver diseases and systemic inflammation, as demonstrated in studies on chromium-induced toxicity (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003e2.1. Bibliometric analysis\u003c/h2\u003e\n\u003cp\u003eTo perform a comprehensive bibliometric review of studies on \"eryptosis\" in the context of \"liver cirrhosis,\" we retrieved data from the Web of Science Core Collection (WOS-CC) and Scopus databases. Our research strategy was designed to encompass a broad spectrum of aspects related to this topic. Data collection was completed in November 2024.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003e2.2. Search strategy\u003c/h2\u003e\n\u003cp\u003eThe search protocol was designed to identify relevant studies on oxidative stress in patients with liver cirrhosis. Specifically, the term \"oxidative stress\" was searched within the title field, while the combination of \"oxidative stress\" and \"liver cirrhosis\" was searched within the abstract field (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Based on the indexing capabilities of the Web of Science and Scopus databases, the search focused on publications from 1991 to 2024, with no additional time restrictions applied.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003e2.3. Inclusion and Exclusion Criteria\u003c/h2\u003e\n\u003cp\u003eInclusion Criteria: Original research articles and review papers published in English that directly addressed oxidative stress in patients with liver cirrhosis were included.\u003c/p\u003e\n\u003cp\u003eExclusion Criteria: Non-research publications (e.g., conference abstracts, editorials, book chapters) and studies that did not explicitly address oxidative stress in patients with liver cirrhosis were excluded. The article selection process is illustrated in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eQueries are used to extract data from Scopus and Web of Science databases (author keywords OR title OR abstract) for a bibliometric analysis of oxidative stress research in liver cirrhosis\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCode\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eQueries\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eNumber of articles\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eScopus\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eWeb of Science\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\"Oxidative Stresses\" OR \"Stress, Oxidative\" OR \"Oxidative Damage\" OR \"Damage, Oxidative\" OR \"Oxidative Damages\" OR \"Oxidative Injury\" OR \"Injury, Oxidative\" OR \"Oxidative Injuries\" OR \"Oxidative Stress Injury\" OR \"Injury, Oxidative Stress\" OR \"Oxidative Stress Injuries\" OR \"Stress Injury, Oxidative\" OR \"Oxidative Cleavage\" OR \"Cleavage, Oxidative\" OR \"Oxidative Cleavages\" OR \"Antioxidative Stress\" OR \"Antioxidative Stresses\" OR \"Stress, Antioxidative\" OR \"Antioxidative Stress\" OR \"Antioxidative Stress\" OR \"Antioxidative Stresses\" OR \"Stress, Antioxidative\"\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e525523\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e66223\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\"Liver Cirrhosis\"\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e419339\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e252702\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e#1 AND #2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e354\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e285\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003e2.4. RStudio and Biblioshiny analyses\u003c/h2\u003e\n\u003cp\u003eThe bibliometric analysis was conducted using RStudio (version 4.4.2), an open-source statistical software platform, in combination with the Bibliometrix R package, a widely used tool for comprehensive bibliometric studies (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e). The analysis, finalized on 17 November 2024, also utilized Biblioshiny, an interactive web-based application integrated with Bibliometrix, to simplify and enhance bibliometric exploration. For improved visualization, charts depicting annual scientific output and average citations per year, originally generated in Biblioshiny, were recreated using Flourish Studio (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://flourish.studio/\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAt this stage of the research, original articles were selected through a two-step process conducted by S.K. and K.B. The selection criteria involved evaluating article titles and abstracts identified via a systematic search strategy. Articles approved by both authors were then subjected to full-text analysis. In cases of disagreement, the final decision was made by a third author, K.K.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003e2.5. Outline of key institutions, influential publications, leading authors, and associated nations\u003c/h2\u003e\n\u003cp\u003eWe developed visual representations to highlight the relationships between the most influential institutions and authors, providing insights into their collaborative efforts. Countries were assessed based on their academic output, represented by the proportion of publications each contributed. Furthermore, we analyzed the level of collaboration among the top 10 most productive nations. To visually represent this cooperation, a map was created to depict the number of publications produced by each country.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003e2.6. Analysis of keyword frequency\u003c/h2\u003e\n\u003cp\u003eA detailed chronological analysis was performed to track the periodic emergence of key terms over time. A TreeMap was created to visually represent the distribution and prominence of the top 10 most frequently occurring keywords. Furthermore, a comprehensive thematic analysis was conducted to identify dominant trends and recurring themes within the selected articles (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003e3.1 Comprehensive overview of the manuscripts\u003c/h2\u003e\n\u003cp\u003eThe study analyzed 627 documents from 358 sources published between 1991 and 2024. The analysis included 6,942 keywords and 1,699 author-provided keywords, reflecting a broad thematic scope and the richness of the research landscape. A total of 3,791 authors contributed to the publications, with only seven documents authored by a single individual, underscoring the highly collaborative nature of this field.\u003c/p\u003e\n\u003cp\u003eOn average, each document involved 8.45 coauthors, highlighting the extensive teamwork characteristic of this research domain. However, international collaboration was observed in only 4.85% of the documents, indicating that most studies were conducted within national or institutional boundaries.\u003c/p\u003e\n\u003cp\u003eThe most cited document, authored by Okuda et al., focused on mitochondrial injury and oxidative stress induced by the hepatitis C virus, garnering an impressive 756 citations and published in Gastroenterology. Recent works, such as those by Zhang et al. (2023) and Xiao et al. (2023), highlight cutting-edge therapeutic approaches involving stem cell-derived exosomes and epigenetic regulation of inflammasomes. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e provides an overview of the top 10 most cited publications on the relationship between oxidative stress and liver cirrhosis.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eTop 10 most cited publications on the relationship between oxidative stress and liver cirrhosis (1991\u0026ndash;2024)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRank\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAuthors (References)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTitle of the document\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eJournal name\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal citations\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDOI\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOkuda et al. (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGastroenterology\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e756\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/gast.2002.30983\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSanyal et al. (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eA Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNew Engl J Med\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/gast.2002.30983\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eH\u0026auml;ussinger et al. (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHepatic encephalopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNat Rev Disease Prim\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e82\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/gast.2002.30983\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eZhang et al.(\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eExosomes derived from human adipose mesenchymal stem cells ameliorate hepatic fibrosis by inhibiting PI3K/Akt/mTOR pathway and remodeling choline metabolism\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNanobiotechnology\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12951-023-01788-4\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHarrison et al. (\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSafety and efficacy of once-weekly efruxifermin versus placebo in nonalcoholic steatohepatitis (HARMONY): a multicenter, randomized, double-blind, placebo-controlled, phase 2b trial\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLancet Gastroenterol Hepatol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S2468-1253(23)00272-8\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eXiao et al. (\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSTING mediates hepatocyte pyroptosis in liver fibrosis by Epigenetically activating the NLRP3 inflammasome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRedox Biol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.redox.2023.102691\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGane et al. (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eThe mitochondrion-targeted antioxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLiver Int\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e294\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1478-3231.2010.02250.x\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChen et al. (\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeep whole-genome analysis of 494 hepatocellular carcinomas\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNature\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41586-024-07054-3\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDrummer et al.(\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCaspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFront Immunol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fimmu.2023.1113883\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDe et al. (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHepatology\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e362\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/he.2000.5789\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003e3.2. Annual analysis of publications\u003c/h2\u003e\n\u003cp\u003eThe analysis of published articles from 1991 to 2024, as illustrated in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, reveals a gradual upward trend in research output. Between 1991 and 2021, the number of published articles remained relatively low, fluctuating below 10 articles per year. A steady increase began in 2005, with periodic minor fluctuations. A significant surge was observed in 2022, with 30 articles published. This upward trajectory continued in 2023 and 2024, with the number of publications rising sharply to 227 and 237 articles, respectively. This remarkable growth, depicted in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, highlights the sustained and growing interest in oxidative stress and liver cirrhosis research.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003e3.3. Countries and affiliations\u003c/h2\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA highlights the top 20 countries by the number of published articles. China leads with over 200 publications, accounting for 31.3% of the total output. However, the United Kingdom stands out as a key hub for collaboration, forming strong research partnerships with countries such as Germany, Italy, and other European nations, as illustrated in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB. This underscores the UK's significant role in global research networks.\u003c/p\u003e\n\u003cp\u003eEuropean countries dominate the collaboration network, showcasing dense interconnections that emphasize the strength of intra-continental cooperation.\u003c/p\u003e\n\u003cp\u003eNorth America: The United States and Canada play prominent roles, actively fostering global research partnerships.\u003c/p\u003e\n\u003cp\u003eAsia and Oceania: Countries in these regions, including India, Saudi Arabia, and New Zealand, are increasingly contributing to international research efforts, reflecting their growing presence in global collaboration networks.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003e3.4. Evolution of publication and citation metrics\u003c/h2\u003e\n\u003cp\u003eThe evolution of publication and citation metrics in the field of oxidative stress and liver cirrhosis research from 1991 to 2024 reflects the growing scholarly interest and recognition of this topic. A detailed analysis reveals significant trends in the annual growth rate of publications. The annual growth rate for publications in this field is calculated at 22.08%, indicating a consistent increase in research output over the decades.\u003c/p\u003e\n\u003cp\u003ePublication Trends: Early research (1991\u0026ndash;2000) primarily focused on foundational studies that identified the relationship between oxidative stress and liver diseases, particularly hepatitis and cirrhosis. From 2001 to 2024, publications sharply increased, driven by advancements in molecular biology, imaging technologies, and therapeutic strategies.\u003c/p\u003e\n\u003cp\u003eCitation Impact: The average number of citations per article during the period was 51.36, signifying the strong influence of these studies on subsequent research. Landmark publications, such as those by Okuda et al. (2002), have amassed hundreds of citations, with the most-cited paper achieving 756 citations.\u003c/p\u003e\n\u003cp\u003eTop Contributing Journals: Leading journals, such as Gastroenterology, Nature, and Hepatology, have been pivotal in disseminating high-impact research. These journals frequently publish groundbreaking studies that drive innovations in understanding oxidative stress mechanisms.\u003c/p\u003e\n\u003cp\u003eAuthor Collaboration: A notable proportion of the research (24.95%) involved international collaboration, highlighting the multidisciplinary and global nature of the field.\u003c/p\u003e\n\u003cp\u003eEmerging Research Themes: In recent years, there has been a shift toward novel therapeutic approaches, including the role of exosomes, antioxidants, and molecular inhibitors targeting specific pathways.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003e3.5. Graphical representation\u003c/h2\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e illustrates the application of Bradford's Law of Scattering to identify the most productive journals in the field of phytomedicine, likely related to oxidative stress and liver cirrhosis. Bradford's Law categorizes journals into three zones based on their contribution to the body of research: a small number of highly productive core sources and a larger number of less productive noncore sources.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n\u003ch2\u003e3.6. Most productive authors, institutions, countries, and their collaboration network\u003c/h2\u003e\n\u003cp\u003eThese institutions include Cairo University (18 articles), Sichuan University (16 articles), Kashan University of Medical Sciences (15 articles), Mansoura University (15 articles), University of Padua (15 articles), Chiang Mai University (14 articles), Benha University (13 articles), King Saud University (13 articles), Pusan National University (13 articles), and Zagazig University (13 articles), reflecting active global research efforts on oxidative stress and liver cirrhosis (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eA). Among the authors, Wang Y. distinguished himself with the highest number of articles (27, 0.21%), followed by UX, who published 25 articles (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003eB).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe increasing body of literature on oxidative stress and liver cirrhosis over the last three decades highlights the growing recognition of the critical role oxidative stress plays in the pathophysiology of liver diseases, particularly cirrhosis. The bibliometric analysis of 627 documents published between 1994 and 2024 revealed a marked rise in scholarly interest since 2005, which can be attributed to several key advancements in molecular biology, imaging technologies, and therapeutic strategies. This trend is indicative of the expanding research efforts to explore the mechanisms of oxidative stress in liver cirrhosis and the subsequent development of potential therapeutic interventions (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe gradual increase in publications, particularly from 2005 onward, aligns with the growing awareness of oxidative stress as a central mechanism in liver damage. The rapid rise in publications since 2022, with over 200 articles per year, underscores the significant progress in this field and reflects an intensifying focus on oxidative stress as a crucial target for both basic and applied research (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The annual growth rate of 22.08% further emphasizes the sustained momentum in this area, showing that the field is increasingly integrated into the broader biomedical research agenda.\u003c/p\u003e \u003cp\u003eNotably, the annual citation rate per article, averaging 51.36 citations, reflects the growing influence of the research outputs. Landmark studies, such as Okuda et al. (2002) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) on mitochondrial injury and oxidative stress in hepatitis C virus-infected patients, have set the foundation for much of the current understanding of oxidative stress in liver diseases. The continuing relevance of these early studies is also evident from their high citation count, which remains a point of reference for newer research.\u003c/p\u003e \u003cp\u003eThe analysis of the geographical distribution of publications indicates that China leads the field, accounting for 31.3% of total publications. This can be attributed to China's significant investments in biomedical research infrastructure and the prioritization of liver disease research (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Furthermore, the United States, the United Kingdom, and several European countries, including Germany and Italy, have played key roles in fostering international collaborations and driving innovations in the field. These nations are home to some of the most influential institutions and researchers, as reflected in their collaborative networks. The strong interconnections between European countries and their expanding collaborations with researchers from Asia and North America highlight a global research network focused on understanding the mechanisms of oxidative stress and its impact on liver cirrhosis.\u003c/p\u003e \u003cp\u003eThe relatively low rate of international collaboration (4.85%) across the documents suggests that, despite the global significance of the topic, much of the research on oxidative stress and liver cirrhosis is still conducted within national or institutional boundaries. However, the increasing trend toward collaboration observed in recent years points to a shift towards more global cooperation, which will be crucial for addressing complex challenges such as therapeutic development and diagnostic advancement.\u003c/p\u003e \u003cp\u003eA chronological analysis of the publication trends revealed several distinct phases in the evolution of research on oxidative stress and liver cirrhosis. Early studies (1991\u0026ndash;2000) focused on establishing the foundational understanding of oxidative stress in liver diseases, with a particular emphasis on its role in liver fibrosis and cirrhosis caused by hepatitis. From 2001 onward, research increasingly incorporated advanced molecular techniques, such as gene expression analysis, proteomics, and advanced imaging technologies, which facilitated a deeper exploration of the cellular and molecular pathways involved in oxidative stress (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRecent studies, particularly from 2020 onwards, have shifted focus towards novel therapeutic approaches. These include the use of stem cell-derived exosomes, antioxidants, and molecular inhibitors targeting specific oxidative stress pathways (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The recognition of exosomes, for example, as vehicles for delivering therapeutic molecules, signals a promising area for future research and therapeutic development (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). The role of epigenetic regulation, particularly concerning inflammasomes and oxidative stress, is another emerging theme that could reshape the therapeutic landscape (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAddressing these challenges is closely tied to the technological revolution in fields such as flow cytometry and microscopy, which enable the identification of diverse factors associated with oxidative stress, as highlighted in Tkachenko A.'s detailed analysis of pathogenesis and the critical mechanisms underlying these processes (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe institutional landscape shows that a small group of institutions, such as Cairo University and Sichuan University, have been particularly productive in contributing to the understanding of oxidative stress in liver cirrhosis. This highlights the importance of a few core research hubs in driving forward the scientific discourse. The leading authors, such as Wang Y. and UX, have made significant contributions to the field, as evidenced by their extensive publication records. These prolific researchers continue to shape the direction of the field through their collaborative efforts and contributions to key studies.\u003c/p\u003e \u003cp\u003eAn important aspect of this bibliometric analysis is the identification of the most influential journals in the field. Journals such as Gastroenterology, Hepatology, and Nature have played a pivotal role in disseminating high-impact research that shapes the field of oxidative stress and liver cirrhosis. The application of Bradford's Law of Scattering reveals a small number of highly productive core journals that consistently publish groundbreaking studies, while a larger number of journals contribute to the literature with less frequent publications.\u003c/p\u003e"},{"header":"5. Future directions and challenges","content":"\u003cp\u003eAs the body of literature continues to grow, several challenges remain in the research landscape. First, there is a need for greater international collaboration to address complex questions related to the pathogenesis of oxidative stress and its role in liver cirrhosis. Although some countries are actively engaged, further efforts to enhance cross-border research initiatives will be essential for advancing the field. Additionally, while much progress has been made in understanding the molecular mechanisms of oxidative stress, the development of effective diagnostic tools and therapeutic strategies remains a critical challenge.\u003c/p\u003e \u003cp\u003eThe increasing interest in novel therapeutic approaches, such as the use of antioxidants and exosomes, holds great promise. However, the need for clinical validation and large-scale trials to assess the efficacy of these strategies is paramount. Moreover, the integration of advanced technologies such as artificial intelligence and machine learning could further accelerate the identification of new therapeutic targets and biomarkers for oxidative stress in liver diseases.\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eThe bibliometric analysis of the past three decades of research on oxidative stress and liver cirrhosis underscores the growing interest and progress in understanding this complex relationship. The significant global contributions, especially from China, the United States, and European countries, reflect the collaborative nature of this research field. Emerging therapeutic approaches, such as stem-cell derived exosomes and molecular inhibitors, represent exciting avenues for future exploration. However, continued international collaboration, technological innovation, and clinical validation are crucial for translating these findings into effective treatments for patients suffering from liver cirrhosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eConceptualization: S.K. and K.B.; data curation: K.K., M.M. and A.M.; formal analysis: S.K. and K.B.; investigation: K.T.; methodology: K.T. and M.M..; project administration: S.K.; resources: K.B.; software: M.M. and N.A.; supervision: S.K. and K.B.; writing\u0026mdash;original draft: K.B.; writing\u0026mdash;review and editing: S.K., K.K., K.T., M.M., N.A. and A.M. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eNofundingwasreceivedforthismanuscript.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eSupporting Information\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eAdditional supporting information can be found online in the Supporting Information section. Tables S1 and S2 provide the search queries for relevant articles from the Scopus and Web of Science databases, respectively. Table S3 presents the R code used to merge data from the Web of Science and Scopus databases. The code imports datasets from both sources, combines them, removes duplicates, and exports the merged data into an Excel file.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBanerjee T, Sar S, Saha S, Baidya A, Sarkar A, Karmakar S et al (2023) Herbal Medicines for the Treatment of Liver Cirrhosis. In: Dhara AK, Mandal SC, editors. Role of Herbal Medicines: Management of Lifestyle Diseases [Internet]. Singapore: Springer Nature Singapore; pp. 185\u0026ndash;209. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/978-981-99-7703-1_10\u003c/span\u003e\u003cspan address=\"10.1007/978-981-99-7703-1_10\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLang F, Qadri SM (2012) Mechanisms and significance of eryptosis, the suicidal death of erythrocytes. Blood Purif 33(1\u0026ndash;3):125\u0026ndash;130\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLang E, Lang F (2015) Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death. Semin Cell Dev Biol 39:35\u0026ndash;42\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChrostek L (2014) Liver fibrosis markers in alcoholic liver disease. World J Gastroenterol 20(25):8018\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePretorius E, Bester J, Vermeulen N, Lipinski B, Gericke GS, Kell DB (2014) Profound Morphological Changes in the Erythrocytes and Fibrin Networks of Patients with Hemochromatosis or with Hyperferritinemia, and Their Normalization by Iron Chelators and Other Agents. Arumugam TV, editor. PLoS ONE. ;9(1):e85271\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlzoubi K, Honisch S, Abed M, Lang F (2013) Triggering of Suicidal Erythrocyte Death by Penta-O-galloyl-β-d-glucose. Toxins 6(1):54\u0026ndash;65\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLang F, Gulbins E, Lerche H, Huber SM, Kempe DS, Foller M (2008) Eryptosis, a window to systemic disease. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 22(5\u0026ndash;6):373\u0026ndash;380\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKurmangaliyeva S, Baktikulova K, Tkachenko V, Seitkhanova B, Shapambayev N, Rakhimzhanova F et al (2024) An Overview of Hexavalent Chromium-Induced Necroptosis, Pyroptosis, and Ferroptosis. Biol Trace Elem Res\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAria M, Cuccurullo C (2017) bibliometrix: An R-tool for comprehensive science mapping analysis. J Informetr 11(4):959\u0026ndash;975\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOkuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM et al (2002) Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122(2):366\u0026ndash;375\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanyal AJ, Bedossa P, Fraessdorf M, Neff GW, Lawitz E, Bugianesi E et al (2024) A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med 391(4):311\u0026ndash;319\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eH\u0026auml;ussinger D, Dhiman RK, Felipo V, G\u0026ouml;rg B, Jalan R, Kircheis G et al (2022) Hepatic encephalopathy. Nat Rev Dis Primer 8(1):43\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Z, Shang J, Yang Q, Dai Z, Liang Y, Lai C et al (2023) Exosomes derived from human adipose mesenchymal stem cells ameliorate hepatic fibrosis by inhibiting PI3K/Akt/mTOR pathway and remodeling choline metabolism. J Nanobiotechnol 21(1):29\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarrison SA, Frias JP, Neff G, Abrams GA, Lucas KJ, Sanchez W et al (2023) Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol 8(12):1080\u0026ndash;1093\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiao Y, Zhao C, Tai Y, Li B, Lan T, Lai E et al (2023) STING mediates hepatocyte pyroptosis in liver fibrosis by Epigenetically activating the NLRP3 inflammasome. Redox Biol 62:102691\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGane EJ, Weilert F, Orr DW, Keogh GF, Gibson M, Lockhart MM et al (2010) The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int Off J Int Assoc Study Liver 30(7):1019\u0026ndash;1026\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen L, Zhang C, Xue R, Liu M, Bai J, Bao J et al (2024) Deep whole-genome analysis of 494 hepatocellular carcinomas. Nature 627(8004):586\u0026ndash;593\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrummer C, Saaoud F, Jhala NC, Cueto R, Sun Y, Xu K et al (2023) Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages. Front Immunol 14:1113883\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F et al (2000) Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatol Baltim Md 31(4):997\u0026ndash;1004\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi S, Hong M, Tan HY, Wang N, Feng Y (2016) Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases. Oxid Med Cell Longev 2016:4234061\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V et al (2017) Oxidative Stress: Harms and Benefits for Human Health. Oxid Med Cell Longev 2017:8416763\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang FS, Fan JG, Zhang Z, Gao B, Wang HY (2014) The global burden of liver disease: the major impact of China. Hepatol Baltim Md 60(6):2099\u0026ndash;2108\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButterfield DA (2004) Proteomics: a new approach to investigate oxidative stress in Alzheimer\u0026rsquo;s disease brain. Brain Res 1000(1\u0026ndash;2):1\u0026ndash;7\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXia C, Dai Z, Jin Y, Chen P (2021) Emerging Antioxidant Paradigm of Mesenchymal Stem Cell-Derived Exosome Therapy. Front Endocrinol 12:727272\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRajput A, Varshney A, Bajaj R, Pokharkar V (2022) Exosomes as New Generation Vehicles for Drug Delivery: Biomedical Applications and Future Perspectives. Mol Basel Switz 27(21):7289\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng X, Sawalha AH (2022) The Role of Oxidative Stress in Epigenetic Changes Underlying Autoimmunity. Antioxid Redox Signal 36(7\u0026ndash;9):423\u0026ndash;440\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTkachenko A (2024) Apoptosis and eryptosis: similarities and differences. Apoptosis 29(3):482\u0026ndash;502\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"West Kazakhstan Marat Ospanov State Medical University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"eryptosis, antioxidant therapy, liver fibrosis, collaboration networks, bibliometric analysis, oxidative biomarkers","lastPublishedDoi":"10.21203/rs.3.rs-5648355/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5648355/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eOxidative stress is a critical factor in the pathophysiology of liver diseases, including chronic conditions and cirrhosis. However, the scientific landscape in this field remains fragmented. This bibliometric analysis aims to systematize existing research, identify major trends, and outline emerging directions. Data from the Scopus and Web of Science databases were analyzed, with a focus on peer-reviewed publications from 1991 to 2023. The key metrics included publication counts, citation analysis, keyword co-occurrence, and thematic mapping. The results revealed substantial growth in publications on oxidative stress and liver diseases over the past two decades. Key research areas include liver fibrosis, alcohol-induced liver damage, nonalcoholic fatty liver disease (NAFLD), and the therapeutic potential of antioxidants. The United States leads research output, demonstrating active collaboration with the United Kingdom, Germany, China, and Saudi Arabia. Emerging contributors, such as India, Egypt, and Brazil, are also gaining prominence, albeit on a smaller scale. Keyword analysis identified new areas of focus, such as \"mitochondrial dysfunction,\" \"antioxidant therapy,\" and \"redox signaling.\" Coauthorship networks highlight the global nature of research, with an increasing trend toward international collaboration. These findings emphasize the need to develop targeted antioxidant therapies, integrate oxidative stress biomarkers into clinical practice, and advance precision medicine approaches. This analysis offers valuable insights into the trajectory of oxidative stress research in liver diseases, providing a foundation for future investigations and clinical applications.\u003c/p\u003e","manuscriptTitle":"A Bibliometric Analysis of Oxidative Stress Research in Liver Cirrhosis: Trends, Hotspots, and Future Directions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-17 13:28:49","doi":"10.21203/rs.3.rs-5648355/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cb047043-934f-4497-9eb1-3aae1bd1d0e0","owner":[],"postedDate":"December 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":41619612,"name":"Immunology"},{"id":41619613,"name":"Critical Care \u0026 Emergency Medicine"},{"id":41619614,"name":"Gastroenterology \u0026 Hepatology"}],"tags":[],"updatedAt":"2024-12-23T07:23:37+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-17 13:28:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5648355","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5648355","identity":"rs-5648355","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}