Navigating the Landscape of MANF Research: A Scientometric Journey with CiteSpace Analysis

This study employs bibliometric analysis through CiteSpace to comprehensively evaluate the status and trends of MANF (mesencephalic astrocyte-derived neurotrophic factor) research spanning 25 years (1997–2022). It aims to fill the gap in objective and comprehensive reviews of MANF research. MANF-related studies were extracted from the Web of Science database. MANF publications were quantitatively and qualitatively analyzed for various factors by CiteSpace, including publication volume, journals, countries/regions, institutions, and authors. Keywords and references were visually analyzed to unveil research evolution and hotspot. Analysis of 353 MANF-related articles revealed escalating annual publications, indicating growing recognition of MANF's importance. High-impact journals such as the International Journal of Molecular Sciences and Journal of Biological Chemistry underscored MANF’s interdisciplinary significance. Collaborative networks highlighted China and the USA’s pivotal roles, while influential figures and partnerships drove understanding of MANF's mechanisms. Co-word analysis of MANF-related keywords exposed key evolutionary hotspots, encompassing neurotrophic effects, cytoprotective roles, MANF-related diseases, and the CDNF/MANF family. This progression from basic understanding to clinical potential showcased MANF’s versatility from cellular protection to therapy. Bibliometric analysis reveals MANF’s diverse research trends and pathways, from basics to clinical applications, driving medical progress. This comprehensive assessment enriches understanding and empowers researchers for dynamic evolution, advancing innovation, and benefiting patients. Graphical Abstract Bibliometric analysis of MANF research. The graphical abstract depicts the bibliometric analysis of MANF research, highlighting its aims, methods, and key results.


Introduction
Mesencephalic astrocyte-derived neurotrophic factor (MANF) also known as arginine-rich mutated in early tumors (ARMET) (Petrova et al. 2003;Sanderson et al. 2009;Shridhar et al. 1996) or arginine-rich protein (ARP) (Evron et al. 1997) was initially discovered in 2003, is an emerging neurotrophic factor (NTFs) in vertebrates that has gained significant attention in medical research (Petrova et al. 2003).MANF exhibits distinct characteristics compared to other NTFs, displaying minimal sequence similarity and representing an evolutionarily ancient protein (Petrova et al. 2003;Palgi et al. 2009b;Bai et al. 2018).It has garnered interest due to its wide expression in both invertebrate and vertebrate species (Wang et al. 2021b(Wang et al. , 2014;;Lindholm et al. 2008;Chen et al. 2012;Palgi et al. 2009a), as well as its cytoprotective effects on neuronal and non-neuronal cell survival and development (Lindholm et al. 2008;Wang et al. 2021b;Kim et al. 2017).MANF plays a crucial role in various physiological processes, particularly during early developmental stages (Wen et al. 2022).Its expression is prominently observed in the central nervous system (Wang et al. 2021b;Kim et al. 2017), where it serves as a protective factor against neuronal degeneration and apoptosis (Lindholm and Saarma 2022;Wang et al. 2021b).Additionally, MANF influences neurite outgrowth and extension (Tseng et al. 2017;Wen et al. 2020), modulates neuron differentiation (Paolino et al. 2018;da Silva and Dotti 2002), and preserves cell migration (Wang et al. 2021b;Kim et al. 2017).Beyond the nervous system, MANF is also expressed in active secretory and metabolic tissues, such as the pancreas, liver, hypothalamus, and pituitary gland (Lindholm et al. 2008;Liu et al. 2015), where it contributes to maintaining metabolic homeostasis and mitigating inflammation (Imran et al. 2017;Sousa-Victor et al. 2019;Liu et al. 2020;Tang et al. 2022).

Quality Assessment
Only English articles that met the inclusion criteria and did not meet the exclusion criteria were included in the analysis.

Quantitative Analysis of Basic Information
The Trend of Annual Publications  publication volume was relatively slow between 1997 and 2010, there has been exponential growth since 2013.This surge can be attributed to advancements in basic medical technology and the persistent exploration of MANF's neuroprotective applications in cell cultures and animal models.As of November 1, 2022, a total of 34 articles have been published, and it is expected that more will follow.The upward trajectory of annual publications underscores the active and promising nature of MANF research.

Published Journal
We identified the top 25 journals based on publication volume in Fig. 2b, out of a total of 202 journals.The International Journal of Molecular Sciences and the Journal of Biological Chemistry were tied for first place with 8 publications each.They were followed by Experimental Neurology and Scientific Reports with 7 publications each and Biochemical and Biophysical Research Communications and Journal of Neuroscience Research both had 6 publications.Figure 2c presents the top 25 Web of Science subject classifications in the field of MANF, Neurosciences ranked first with 96 publications, followed by Biochemistry and Molecular Biology with 59 publications.The 25th category was Biochemical Research Methods and Gastroenterology Hepatology with 4 publications.In terms of publishing units, as shown in Fig. 2d, Elsevier ranked first with 93 publications, followed by Springer Nature with 67, Wiley with 37, Frontiers Media Sa with 29, MDPI with 11, and Soc Neuroscience with 8 publications.Based on the above analysis, it is evident that MANF research primarily focuses on Neurology and Biochemistry, and most publications are associated with Elsevier and Springer Nature.While the publication peak in this field may not be as high as in other areas, the value and significance of the MANF field are increasingly recognized by scientific researchers.

The Cooperation Network of Countries and Institutions
Our statistical analysis focused on MANF-related papers from various countries and regions, aiming to identify influential institutions and their collaborative networks.Between 1997 and 2022, around 44 countries and regions contributed to MANF-related publications.Notably, Table 1 highlights the top 10 countries and regions in terms of publication volume, China leads with 138 articles, followed by the USA with 98.China's Cluster ID of 12.5 in 2006 suggests concentrated publishing activity, while the USA's Cluster ID of 19.5 hints at early involvement in MANF research.Finland achieved a Cluster ID of 10.5 in 2007 and Japan reached 13.5 in 1998, indicating their contributions and clustering patterns.
Figure 2a highlights countries with the strongest citation bursts.The USA exhibits a burst strength of 5.24 from 1997 to 2003 and Japan records a burst strength of 5.39 from 1998 to 2014, reflecting their historical strengths in MANF research.Figure 3b portrays cooperative relationships among countries.China, the USA, Finland, and Japan, characterized by higher publication volumes, have larger nodes.Notably, robust collaborations are evident between Japan and Finland, denoted by thicker connecting lines.Centrality analysis ranks the USA highest, trailed by Finland and China, underlining their influential roles and strong field connections.
Regarding institutional cooperation, we examined 321 publishing institutions (Table 2; Fig. 3c).The top 10 institutions include five from China and two from the USA, reinforcing their dominance.The University of Helsinki (Finland) leads with 73 publications, while others also have significant contributions.Notably, Anhui Medical University (China) and the Chinese Academy of Sciences (China) are prominent publishers.Collaboration analysis unveils close ties among key contributors.The University

The Network of Author Cooperation
Using CiteSpace, we analyzed the top 20 authors (Fig. 4a; Table 3) out of 563 authors involved in MANF research.
Professor Saarma Mart from the University of Helsinki ranked first with 44 articles, followed by Lindholm from Northwestern University with 27 articles, and then Thrie Lindahl Maria from the University of Linköping with 25 articles.Examining their cooperation, we observed a decentralized author network, with closer relationships among a few scholars and larger groups remaining more distant (Fig. 4b).These cooperative relationships were primarily based on institutional or academic affiliations.
Another notable collaboration is observed between Fang Shengyun, Shen Yuxian, and Wangdong, scrutinizing MANF's impact on macrophages and visceral function (Shen et al. 2022).Notably, the analysis pinpoints authors with strong citation bursts (Fig. 4c), like Peranen Johan's burst strength of 5.24 from 2008 to 2011, and Fang Shengyun's burst strength of 5.39 from 2008 to 2015, suggesting their forthcoming influence in MANF research.The collaborative endeavors of these authors have significantly advanced MANF comprehension, its mechanisms, therapeutic applications, and its relevance across various disorders.Sustained collaboration and knowledge exchange among these authors will propel the field further.In summary, our analysis of basic information in MANF research has shown a steady rise in annual publications, particularly since 2013, driven by advances in medical technology.Key journals and subject categories underscore the multidisciplinary nature of this field.Collaborative networks highlight the leading roles of China and the USA, with institutions like the University of Helsinki and authors such as Professor Saarma Mart contributing significantly.This information equips researchers with insights to align their work strategically, emphasizing collaboration and multidisciplinary approaches.It offers a compass for navigating the evolving MANF landscape, guiding new directions and innovative applications.(4.61 strength, 2020-2022).These bursts mirror the dynamic essence of MANF research, signifying the ascendancy of specific themes as their significance gains traction.By combining the keyword timeline view and co-citation patterns (Fig. 5c), we observed a shift in MANF research focus over time.Initially, research primarily centered on the cytoprotective effects of MANF, particularly in dopamine neurons.However, recent years have seen a shift toward investigating MANF's clinical benefits and potential therapeutic applications across various diseases.This expansion of focus signifies MANF's growing relevance as a potential treatment strategy beyond neuroprotection.
The analysis of keyword co-occurrence and bursts provides valuable insights into research hotspots and the evolving landscape of MANF research.It highlights the broadening scope of research from cytoprotection to potential clinical applications in different diseases.

Strategic Coordinate Diagram in the Field of MANF
We constructed a strategic coordinate diagram based on re-analyzed keyword data from CiteSpace to predict future research hotspots and trends in the field of MANF.The diagram consisted of four quadrants representing different research clusters (Fig. 5d; Table 5).In the first quadrant, we identified core research clusters with high novelty and attention indicators.The CDNF/MANF family (16#) emerged as a focal point, indicating its ongoing significance in research.The second quadrant encompassed potential research clusters with higher novelty but lower attention indicators, The strategic coordinate diagram provides researchers with a roadmap for future exploration.Core research clusters, such as the CDNF/MANF family, remain central and warrant continued investigation.Additionally, potential research clusters with high novelty indicators, like brain barrier dysfunction, metabolism diseases, and cell injury, offer exciting avenues for further inquiry.These clusters represent emerging hotspots where researchers can make novel contributions.Additionally, research has highlighted the involvement of MANF in various diseases and pathogenic processes across multiple tissues and systems.Future research hotspots are expected to explore the therapeutic potential of MANF in different diseases (Yang and Gao 2020;Liu et al. 2021;Kovaleva and Saarma 2021), including neurodegenerative diseases (Liu et al. 2021;Kovaleva and Saarma 2021), brain barrier dysfunction (Gao et al. 2020), metabolism diseases (Danilova et al. 2019;Cordero-Llana et al. 2015), acute kidney injury (Yang and Gao 2020;Liu et al. 2021;Kovaleva and Saarma 2021), cognitive deficits (Liu et al. 2022;Zhang et al. 2023), depression (Liu et al. 2022;Zhang et al. 2023), inflammation (Sun et al. 2022;Liu et al. 2022;Zhang et al. 2023Zhang et al. , 2022)), and cardiovascular risk (Zhang et al. 2022).
Conversely, marginal research areas with lower novelty and attention indicators may indicate areas where shifting focus could be advantageous.Investigating extracellular and intracellular mechanisms related to MANF, such as cell injury, oxidase deficiency, convection-enhanced delivery, calcium homeostasis, extracellular polysaccharides, and intracellular trafficking, will also be important.This approach ensures that research efforts are directed toward promising directions with potential real-world applications.
Ultimately, researchers can leverage these insights to guide their studies and contribute to the advancement of MANF research.By delving deeper into the mechanisms of the CDNF/MANF family, exploring therapeutic applications, and investigating emerging hotspots, researchers have the opportunity to uncover new knowledge and potentially revolutionize disease treatment strategies.The evolving landscape of MANF research provides a dynamic platform for scientific innovation and discovery.

Analysis of Reference
The analysis of references in the field of MANF provides valuable insights into citation patterns and influential works (Table 6).One notable reference that has garnered significant interest is Richman et al. (2018), with the highest frequency of 66 citations.This reference holds importance and impact, as indicated by its half-life of 1.5 and centrality of 0.02. Figure 6a illustrates the cooperative relationships among MANF references over time, with the increasing number and size of nodes representing growing influence and collaboration among researchers.The color of the nodes represents the referenced years, while the intricate connection lines depict the complexity of the relationships between references.Arranging chronologically from left to right shows an increasing number and size of nodes over time, along with a growing quantity and complexity of connection lines.The intricate connection lines signify the complexity of these relationships.
A chronological analysis of the references highlights several significant works in the field.Notable references include Voutilainen et al. (2009), Lindholm and Saarma (2010)   burst value (16.01) is associated with Lindholm and Saarma (2010), suggesting MANF's potential as a therapeutic approach for neurodegenerative diseases by promoting the survival, development, maintenance, and differentiation of neurons (Lindholm and Saarma 2010).Overall, the analysis of references provides valuable insights into the influential works, emerging trends, and research directions in the field of MANF.Researchers can refer to these references to stay updated on the latest developments and contribute to the advancement of MANF research.
The co-word analysis of MANF-related keywords revealed key hotspots driving the field's evolution.These include the endoplasmic reticulum's role, MANF as a neurotrophic factor, its cytoprotective effects, focus on MANFrelated diseases and their mechanisms, and exploration of the CDNF/MANF protein family.This analysis highlights a progression from basic understanding to clinical applications, underscoring MANF's potential in diverse contexts, from cellular protection to therapeutic interventions.Foundational studies served as beacons, MANF's initial recognition stemmed from its exceptional capacity to enhance the survival of dopaminergic neurons in vitro.
This intricate network of pathways conferred upon MANF an array of valuable properties, ranging from promoting cell survival, thwarting apoptosis (Zhang et al. 2017), and bolstering antioxidant defenses to regulating autophagy and facilitating neurite outgrowth (Liu et al. 2022;Sun et al. 2017;Voutilainen et al. 2015).Notably, the subsequent sections offer an in-depth exploration of MANF's multifaceted roles and the underlying mechanisms driving its protective effects across a spectrum of diseases (Liu et al. 2022).
MANF offers diverse neuroprotection in neurodegenerative diseases and ischemia.In Parkinson's models, MANF manages cellular stress via endoplasmic reticulum regulation (Apostolou et al. 2008;Yu et al. 2021) and activates antioxidant pathways through PI3K/Akt/GSK3β and AMPK/mTOR pathway to enhances mitochondrial function (Apostolou et al. 2008;Oh-Hashi et al. 2012;Yang et al. 2020).Notably, elevated blood levels of MANF in Parkinson's disease patients suggest its potential as a diagnostic biomarker (Fu et al. 2021).Similarly, in ischemia, MANF plays a role in curbing neuronal apoptosis by orchestrating UPR-related genes (such as GRP78, phosphorylated IRE1, and XBP1s) (Yang et al. 2014b) and activating the Akt/MDM2/P53 pathway (Airavaara et al. 2009;Zhao et al. 2013).Moreover, MANF promotes neurite outgrowth through the Akt/mTOR and Erk/mTOR pathways (Airavaara et al. 2009;Zhao et al. 2013).Its influence extends to the blood-brain barrier, where it preserves tight junctions and dampens inflammation via TLR4/MyD88/ NF-κB pathways (Han et al. 2022).Additionally, MANF contributes to post-ischemic recovery through pro-angiogenic effects and increased cerebral blood flow, supported by its interaction with vascular endothelial growth factor (VEGF) (Gao et al. 2020).The multifaceted neuroprotection offered by MANF underscores its potential as a promising avenue for further research in neurodegenerative diseases and ischemia-related conditions.
Beyond its neuroprotective roles, MANF plays a pivotal role in maintaining metabolic equilibrium.Its connection to age in type 1 diabetes (T1D) patients highlights its significance in preserving β-cell function (Weir and Bonner-Weir 2013).MANF counters ER stress-induced impairment and fights inflammation-triggered apoptosis by repressing NF-κB (Hakonen et al. 2018).Moreover, MANF finely tunes hypothalamic insulin signaling via PIP4k2b, influencing food intake and body weight (Hakonen et al. 2018;Montaser et al. 2021a).This intervention results in decreased obesity and inhibition of fatty acid biosynthesis and cholesterol production, contributing to a healthier metabolic profile.MANF's diverse functions position it as a promising candidate for therapeutic interventions in metabolic disorders.
Regarding the CDNF/MANF family's pivotal role highlighted by the strategic coordinate diagram analysis, their discovery in the early 2000s has not led to a complete grasp of their fundamental biology and cytoprotective mechanisms (Lindahl et al. 2017;Pakarinen et al. 2022).Notably, both CDNF and MANF display neuroprotective effects that extend beyond Parkinson's disease, embracing conditions like cerebral ischemia and spinocerebellar ataxia (Lindholm and Saarma 2010).Leveraging knockout models of these proteins across diverse organisms holds the promise of unveiling their multifaceted functions and therapeutic potential across a wide spectrum of neurodegenerative disorders (Pakarinen et al. 2022;Kordower and Bjorklund 2013).In conclusion, the comprehensive analysis of keyword distribution and the strategic coordinate diagram provides invaluable insights into evolving research trends, emerging areas, and potential pathways, thus significantly enriching the dynamic panorama of MANF research.
The analysis of MANF-related references uncovers important trends and impactful works.Richman (2018) reference stands out for its high citations, indicating its importance.Noteworthy works like Voutilainen et al. (2009) and Lindholm and Saarma (2010) emerge in the chronological view, enriching MANF understanding.Burst trends, exemplified by Lindahl et al. (2014) and Lindholm and Saarma (2010), underscore MANF's potential in β-cell growth and neurodegenerative disease treatment.This analysis guides researchers in tracking trends and advancing MANF research.
In conclusion, this comprehensive analysis provides valuable insights into MANF research trends, emerging areas, and potential directions.The dynamic nature of MANF's roles, from fundamental mechanisms to clinical applications, promises exciting possibilities for medical advancements.
Researchers are empowered to contribute significantly to the ever-evolving landscape of MANF, ultimately benefiting patients and medical progress.

Limitation
This study's quantitative approach using the Web of Science database has limitations.It might miss relevant research from other sources.The analysis timeframe and language focus might exclude recent developments and non-English research, narrowing the scope of findings.

Figure
Figure 2a displays the annual publication volume trend for papers related to MANF from January 1, 1997 to November 1, 2022.The data reveals a steady increase in the number of publications on MANF over the years.Since 2011, there have been over 10 articles per year, with a peak of 47 articles in 2020.While the growth in

Fig. 2 a
Fig. 2 a Annual publications in the field of MANF.b The top 25 journals in the field of MANF.c The top 25 Web of Science subject classifications in the field of MANF.d The top 25 publication units in the field of MANF

Fig. 3 a
Fig. 3 a The top 2 countries and regions with the strongest citation bursts in the field of MANF.b The cooperative relationship between countries and regions in the field of MANF.c The cooperative relationship between institutions in the field of MANF

Fig. 4 a
Fig. 4 a The top 20 authors in the field of MANF.b The cooperative relationship between authors in the field of MANF.c The top 2 authors with the strongest citation bursts in the field of MANF

Fig. 5 a
Fig. 5 a The cooperative relationship between keywords in the field of MANF.b The top 8 keywords with the strongest citation bursts in the field of MANF.c Keywords timeline view in the field of MANF.d Strategic coordinate diagram in the field of MANF , Glembotskl et al. (2012), Airavaara et al. (2012), Henderson, Lindahl et al. (2014), Chen et al. (2015), Cordero-Liana et al. (2015), Neves, Lindahl et al. (2017), Tsang et al. (2017), Matlik et al. (2018), and Yan et al. (2020).These references contribute to the evolving knowledge and understanding of MANF. Figure 6b presents a clustering network of references, grouping them based on subject areas or focal points.Each cluster represents a specific topic or theme, with core references marked for their high centrality and frequency.The sub-clusters cover various aspects of MANF research, such as neuronal survival (0#), MPTP treatment (1#), neurotrophic factors (2#), and more.
Figure 6c highlights references with high burst values, indicating emerging trends in MANF research from 2008 to 2022.Lindahl et al. (2014) stands out with a burst value of 16.51, confirming MANF's potential to enhance and restore β-cell proliferation (Lindahl et al. 2014).Another significant

Fig. 6 a
Fig. 6 a The cooperative relationship between references in the field of MANF.b The cooperative relationship between reference clusters in the field of MANF.c The top 25 references with the strongest citation bursts in the field of MANF

Table 1 The
of Helsinki and the Chinese Academy of Sciences hold central roles (centrality values of 0.2 and 0.13), emphasizing their influence in MANF research.The study highlights China and the USA's leading roles in both publication volume and institutional impact, offering insights into the global MANF research landscape.

Table 3
The top 10 authors in the field of MANF

Table 4
The top 10 keywords in the field of MANF

Table 5
Name of clusters in Fig.5c

Table 6
The top 10 references in the field of MANF this thorough analysis of 353 MANF-related articles spanning 1977 to 2022, quantitative and visual techniques were employed to unveil the field's diverse dimensions.Trends in annual publications reflected a consistent rise, underlining growing recognition of MANF's significance.Notably, prestigious journals such as the International Journal of Molecular Sciences and Journal of Biological Chemistry featured prominently, highlighting MANF's interdisciplinary nature.Collaborative networks revealed China and the USA's pivotal roles, while influential figures like Professor Saarma Mart and impactful partnerships drove understanding of MANF's mechanisms