Mapping ophthalmic research on glycosylation and glycation: a PRISMA-compliant bibliometric and co‑citation analysis

Abstract

Background:

Enzymatic glycosylation and non-enzymatic glycation contribute significantly to the pathogenesis of major ocular diseases, particularly diabetic retinopathy (DR), age-related macular degeneration (AMD), glaucoma, and cataract. However, the knowledge structure and developmental trajectory of glycosylation-related research in ophthalmology remain unclear.

Methods:

The literature on the role of enzymatic glycosylation and non-enzymatic glycation modification in ophthalmic diseases from 1997 to 2024 was searched in the core database of Web of Science. Bibliometrics analysis software VOS viewer (version 1.6.20), Citespace (version 6.1.R1), Scimago Graphica (version 6.1.R1), Microsoft Excel 2021.

Results:

This study analyzed 3,221 publications, all results are available on January 4, 2025. Biochemistry & Molecular Biology was the primary subject area. Research has evolved from early exploration of advanced glycation end products and protein kinase C pathways toward inflammation, biomarker discovery, and risk prediction in specific ocular disorders. Increasing attention has also been directed toward glycosylation-based diagnostic markers and potential therapeutic targets.

Conclusion:

This bibliometric analysis provides an ophthalmology-centered overview of glycosylation and glycation research, identifying DR as the primary research hub while highlighting emerging translational directions in retinal and other ocular diseases.

ARTICLE HIGHLIGHTS

• This study presents comprehensive bibliometric analysis of glycosylation and glycation research in ophthalmology from 1997 to 2024.

• United States leads in both publication output and citation impact, with Harvard University being the most prolific institution.

• Research focus has shifted from AGEs and oxidative stress toward inflammatory mechanisms, risk assessment, and biomarker development.

• Diabetic retinopathy remains the central disease model, but there is a growing interest in age-related macular degeneration and glaucoma.

• Interdisciplinary collaboration among biochemistry, ophthalmology, and endocrinology is a key driver of research progress.

• Future research should extend glycobiology approaches to understudied areas such as ocular surface diseases and tear film glycomics.

PLAIN LANGUAGE SUMMARY

Abnormal glycosylation and glycation of ocular proteins can significantly influence the occurrence and development of various ocular diseases. In this study, we found about 3000 papers about “glycosylation and glycation” and “ocular diseases” from 1997 to 2024 and made a simple picture sheet. The sheet shows:

• The number of research on this topic have been increasing rapidly, indicating that it has become a hotspot in ophthalmology research.

• The vast majority of research mainly focuses on diabetic retinopathy (the most common ocular complication of diabetes).

• The United States, Japan and China are the countries that have published the most related papers. Top academic institutions such as Harvard University have made significant contributions in this field.

• In addition to diabetic retinopathy, researchers have begun to pay more attention to the role of “glycosylation and glycation” in other ocular diseases such as ocular surface diseases, keratoconus, glaucoma, age-related macular degeneration, retinitis pigmentosa, as well as new associated factors such as “insulin resistance” and “inflammation”.

• In-depth research on the regulation of abnormal glycosylation and glycation of ocular proteins is of great significance for the diagnosis and treatment of related ocular diseases, and might be provide novel therapeutic strategies and methods for the early detection and treatment of related ocular diseases.

1. Introduction

Protein post-translational modification is a key mechanism to regulate protein function, localization and stability. Among them, the glycosylation of proteins, especially glycosylation, is a crucial and highly complex process. In the field of complex ophthalmic diseases, enzymatic glycosylation and non-enzymatic glycation have gradually emerged and become a key factor of concern. In organisms, the binding of proteins to sugars is mainly achieved through two distinct pathways: one is highly specific, enzyme-driven glycosylation, and the other is a random, non-enzymatic glycosylation reaction [1]. Glycosylation and glycosylation are two different protein post-translational modification processes in mechanism and biological significance. They play a key and complex role in the occurrence and development of ophthalmic diseases.

Glycosylation is a protein post-translational modification that occurs mainly in the endoplasmic reticulum and Golgi. It influences protein stability, cell adhesion, and signaling [2]. This process follows a specific glycosylation motif, which accurately covalently connects a complex carbohydrate chain to a specific residue of the protein to form an N-linked or O-linked glycan chain [3]. This modification is essential for maintaining the correct folding, stability, intracellular localization and functional activity of proteins. It is widely involved in various physiological processes such as cell signal transduction, immune response and so on [4]. However, abnormalities in the glycosylation process are associated with a variety of disease states, and changes in specific glycosylation patterns can be used as potential disease biomarkers [5]. Glycosylation is a non-enzymatic pathological process. It is a random chemical reaction between reducing sugar and free amino group of protein in the environment of hyperglycemia or oxidative stress (OS) and finally forms AGEs. The reaction rate is directly affected by the concentration of sugar and has no enzymatic specificity. The accumulation of AGEs will lead to protein cross-linking, loss of function, and cause OS and inflammatory response, thus playing a central role in pathological processes such as aging, diabetic complications, and neurodegenerative diseases.

In ophthalmology, these two modification pathways are particularly significant and often interrelated. Abnormal glycosylation may contribute to cataract, DR, and AMD by altering lens proteins, retinal vascular endothelial receptors, and extracellular matrix composition [6,7]. Meanwhile, accumulation of AGEs in ocular tissues promotes diabetic cataract, retinal microangiopathy, and glaucomatous optic nerve injury through cellular dysfunction and inflammatory activation [8]. Importantly, the pathological impact of glycosylation and glycation within the eye exhibits tissue-specific characteristics, largely due to the specialized anatomical and physiological features of ocular structures, including high metabolic demand, complex barrier systems, immune privilege, and limited regenerative capacity. In the retina, chronic hyperglycemia promotes AGE accumulation and activation of the AGE–RAGE signaling axis. Binding of AGEs to RAGE on endothelial and neuronal cells triggers oxidative stress, inflammatory cascades, vascular dysfunction, and breakdown of the blood–retinal barrier, constituting a central pathogenic mechanism in DR [9].

Within the retinal pigment epithelium (RPE), precise enzymatic glycosylation is essential for photoreceptor outer segment phagocytosis, complement regulation, and retinal homeostasis [10,11]. Aberrant glycosylation patterns may impair these processes and enhance complement-mediated inflammation, thereby contributing to (AMD. At the ocular surface, mucin-type O-glycosylation maintains tear film stability and epithelial glycocalyx integrity [12]. Disruption of these glycosylation patterns compromises barrier function and predisposes to dry eye disease and infectious keratitis. In the lens, non-enzymatic glycation of crystallin proteins results in cross-linking and aggregation, leading to loss of transparency and cataract formation [13]. The avascular structure and extremely low protein turnover of the lens render it particularly susceptible to cumulative glycation damage [14]. Collectively, these tissue-specific mechanisms highlight the unique vulnerability of ocular tissues to dysregulated glycosylation and glycation, underscoring their clinical significance in ophthalmology.

The core difference between the two is that glycosylation is a specific physiological regulation of enzymatic catalysis, while glycosylation is a random pathological damage of non-enzymatic catalysis. In-depth elucidation of the specific mechanism and correlation of these two modifications in the eye is of great significance for understanding the pathological process of related diseases and developing new prevention and treatment strategies. The purpose of this study is to visualize the academic output in the field of enzymatic glycosylation and non-enzymatic glycation research through systematic bibliometric analysis, focusing on the analysis of publications outputs and citations, disciplinary categories, number of papers published by national institutions, highly cited papers, highly co-cited papers, keyword co-occurrence, keyword mutation analysis.

2. Materials and methods

2.1. Data source and search

The articles and reviews regarding the role of glycosylation and glycation in ophthalmic diseases were collected from the Web of Science Core collection, which includes a variety of influential journals from different academic fields. In addition to providing basic information such as title, author, institution, country or region, and author keywords, it also provides a detailed reference section. To ensure that only the highest-quality academic journals are included, the Web of Science core collection is used. In the present study, the search strategy was as follows: TS=((glycosylation OR “glycosylation modification” OR glycosylate OR “N-glycosylation” OR fucosylation) OR (glycation OR “advanced glycosylation end product*” OR AGEs)) AND TS=(ophthalm* OR eye OR ocular OR retin* OR uveitis OR keratitis OR “macular degeneration” OR glaucoma OR orbitopathy) AND PY=(1997–2024) AND DT=(Article OR Review) AND LA=(English). A total of 3221 documents were exported, and the retrieved documents were exported in the form of all records and references and saved as plain text files. We collected Titles, authors, journals, year of publication, keywords and abstracts, citations along with primary information on the top 10 most cited articles from the WOS analysis results and citation reports. Figure 1A displays the flow chart of the whole study [15]. The literature identification and screening process was conducted in accordance with the PRISMA 2020 reporting framework to ensure transparency and reproducibility in study selection.

Figure 1.

(A) Flowchart of the study selection process; (B) Annual number of publications from 1997 to 2024; (C) Annual citation counts of publications from 1997 to 2024.

2.2. Data analysis

Two bibliometric software tools, Citespace and VOSviewer, were employed to visualize and analyze key elements in this field, including countries, institutions, authors, references, and keywords. VOSviewer is a dedicated program for constructing and viewing bibliometric maps. It enables the creation of author or journal networks based on collaboration data, as well as keyword maps derived from co-occurrence data. The software offers three visualization modes: network, overlay, and density views. It supports various analytical approaches, such as cooperation network analysis, co-occurrence analysis, citation analysis, bibliographic coupling, and co-citation analysis. In these maps, nodes are defined by three main attributes: size, color, and connecting lines. Node size corresponds to its weight-which may represent the number of publications, citations, or total link strength-with larger nodes indicating higher weight. Line width reflects the strength of collaboration or association between nodes, such as co-authorship, citation, or co-occurrence links.

In overlay visualization, a color bar indicates temporal progression, allowing intuitive observation of collaborative relationships across different years [16]. CiteSpace is a Java-based application designed for dynamic visualization of bibliometric networks over time. It excels at detecting citation bursts from highly cited references and keywords within specific periods. The tool aids in understanding knowledge domains, identifying research frontiers and emerging trends, and forecasting future developments [17]. Notably, CiteSpace emphasizes the connections between knowledge areas. By tracking the evolution of scholarly knowledge, it provides an intuitive overview of research hotspots and frontiers, thereby offering insights into potential future directions in the field [18]. For this study, VOSviewer (version 1.6.19) and CiteSpace (version 6.2.R4) were utilized to generate co-authorship, co-citation, and keyword co-occurrence maps. In these visualizations, node size reflects item weight, and edge width indicates link strength. Data processing and graph creation were additionally supported by Microsoft Excel (version 2021) and Scimago Graphica (version 6.1.R1).

3. Results

Only research articles and review articles are included in this study. After a preliminary search, we will automatically and manually exclude entries for the following types of records: Meeting Abstract, Proceeding Paper, Book Chapter, Editorial Material, Correction, Letter, Retracted Publication, and Early Access status.

3221 articles were retained, articles accounted for 78% of the total number of articles, followed by review articles accounted for 22% of the total number of articles.

3.1. Analysis of publications outputs and citations

As shown in Figure 1B, the annual publication and citation counts were analyzed using a line chart to illustrate longitudinal trends in the field. In terms of publication output, the period prior to 1998 was characterized by a limited number of publications, indicating that the field was still in a nascent stage with relatively low academic attention and research investment. Between 2000 and 2009, a marked increase in the volume of published papers was observed, reflecting a period of accelerated growth and rising scholarly interest. This phase was accompanied by a significant expansion in research activity and a growing body of findings. From 2010 to 2024, publications continued to rise steadily, suggesting that the field has maintained sustained research momentum, with ongoing developments in both the depth and breadth of investigative efforts.

As depicted in Figure 1C, the annual citation counts of studies on glycoprotein modification in ophthalmic diseases exhibited consistent growth from 1997 to 2024. This upward trajectory signifies that research in this area has garnered increasing recognition and engagement from the scientific community, reflecting an enhancement in both the quality and impact of the published work. A notable peak occurred in 2021, with 13,759 citations, underscoring a period of particularly high influence and visibility within the field (Figure 2).

Figure 2.

(A) Main countries distribution and collaboration. (B) Overlay visualization of citation, the weight was document; (C) Overlay visualization of co-authorship analysis for countries, the weight was citation.

3.2. Discipline categories

As shown in Table 1, the top 10 disciplinary categories reveal the key research domains and their contributions to the study of glycosylation in ophthalmic diseases. Biochemistry & Molecular Biology ranks first with 750 publications and an H‑index of 89. The growth in citations-from 2,119 in 2020 to 3,058 in 2024-reflects the expanding influence and sustained scholarly attention in this area, underscoring its strong activity in both basic and applied research and its cross‑disciplinary reach spanning biology, medicine, and chemistry. Ophthalmology follows with 542 articles and an H‑index of 83, indicating substantial research focus on the diagnostic, therapeutic, and fundamental aspects of ocular diseases. Notably, Endocrinology & Metabolism, though comprising 443 articles, achieves the highest H‑index (91), suggesting a particularly high impact in this subfield, likely driven by influential studies on mechanistic and clinical intersections between metabolic regulation and disease.

Table 1.

The top 10 discipline categories.

No.	Discipline categories	Publications	Citations (five years)					H-Index
			2020	2021	2022	2023	2024
1	Biochemistry Molecular Biology	750	2,119	2,378	2,549	2,620	3,058	89
2	Ophthalmology	542	2,371	2,665	2,453	2,124	2,192	83
3	Endocrinology Metabolism	443	2,248	2,698	2,592	2,418	2,560	91
4	Pharmacology Pharmacy	302	1,068	1,310	1,338	1,207	1,229	61
5	Cell Biology	269	1,103	1,269	1,300	1,239	1,320	62
6	Medicine Research Experimental	230	859	982	937	833	1,003	54
7	Genetics Heredity	171	484	544	403	367	405	51
8	Neurosciences	167	463	605	554	496	487	45
9	Multidisciplinary Sciences	151	403	482	653	709	745	38
10	Biophysics	119	324	356	363	320	310	40

Other relevant disciplines include Pharmacology & Pharmacy, Cell Biology, Medicine Research & Experimental, Genetics & Heredity, and Neurosciences, each contributing a distinct perspective and demonstrating considerable academic recognition. The presence of these diverse fields highlights the interdisciplinary nature of glycosylation research in ophthalmology. Such cross‑disciplinary engagement not only deepens the understanding of domain‑specific questions but also fosters the development of novel theories, technologies, and methodologies, thereby propelling broader scientific progress.

3.3. Analysis of most productive countries

A total of 88 countries or regions have contributed to the research on glycosylated protein modification in ophthalmic diseases. The United States leads in both publication output and citation impact, with 1,211 publications and 88,715 citations. Japan ranks second in terms of publications (396), followed by China (386), the United Kingdom (339), and Germany (270). Notably, Belgium, though publishing a relatively smaller number of papers (55), has achieved 6,612 citations, resulting in a high citation per paper ratio of 120.22. This indicates that Belgian research in this field enjoys substantial academic recognition and influence. Among the top 20 contributing countries or regions, ten are located in Europe and six in Asia, reflecting a strong geographical concentration of research activity.

As shown in Figure 3A, the global distribution and collaborative networks among major contributing countries are visualized. Figure 3B illustrates distinct regional cooperation patterns: red nodes-including Japan, India, Pakistan, Greece, and South Korea-demonstrate close collaborative ties, highlighting strong regional and multilateral engagement in Asia. Yellow nodes, such as Germany, Spain, Italy, Finland, and the Netherlands, are primarily concentrated in Europe, indicating cooperation largely shaped by European research frameworks. Blue nodes, comprising Portugal, Brazil, Argentina, Switzerland, and Denmark, also form a tightly connected collaborative cluster. The timeline analysis reveals that the United States, Japan, France, the United Kingdom, Germany, and the Netherlands have been consistently active over time. Furthermore, as depicted in Figure 3C, collaboration during 2010–2015 was strongest within Europe and North America, while participation from East Asia has grown noticeably since 2015. The overlay maps also point to potential future cooperation areas, such as countries in Central Asia and West Africa, which could be strategic directions for expanding international research partnerships. Through these visualizations, key collaborative relationships between countries and regions can be clearly identified. Such analyses serve as valuable decision-support tools for policymakers and research managers, aiding in the identification of potential partners and the understanding of international cooperation patterns. By revealing collaborative models and emerging trends, these tools provide evidence-based insights to foster and strategically guide global scientific collaboration.

Figure 3.

(A) Overlay visualization of citation analysis for institutions, the weight was document; (B) Overlay visualization of co-authorship analysis for institutions, the weight was citation; (C) Overlay visualization of citation for authors, the weight was citation; (D) Co-authorship analysis for authors, the weight was citation.

3.4. Analysis of the most prolific institutions

Overall, 3239 published institutions have formed several significant cooperation clusters, and the link strength within and between clusters reflects the characteristics of knowledge flow and resource integration. As shown in Figures 3A and 3B, this study reveals the global institutional collaboration in the field of glycosylation protein modification in ophthalmic diseases through cooperative network analysis. Table 2 shows the top 10 productive institutions.

Table 2.

The top 10 productive institutions.

No.	Institution	Documents	Citations	H-Index
1	Harvard University	109	15051	51
2	University System of Ohio	109	8023	43
3	Harvard Medical School	91	9927	51
4	Case Western Reserve University	89	6856	39
5	University of London	87	6397	41
6	University of California System	85	8827	43
7	Institut National De La Sante Et De La Recherche Medicale Inserm	83	4611	35
8	Kurume University	74	4274	39
9	Queens University Belfast	69	6400	44
10	University College London	64	4830	34

Among the leading institutions, Harvard University (109 articles) and its affiliated Harvard Medical School 91 articles) serve as purple nodes, showing a wide range of international cooperation links. The Ohio University system (109 articles) and the University of California system (85 articles, with a total of 8827 citations and an average of 103.85 citations per article) are also in the core connection position in the network. The number of citations per article in the University of California system is prominent, indicating that its research results have a high academic influence. As one of the red nodes, Queen’s University of Belfast (69 articles, 6400 citations in total, 92.75 citations per article) maintains close cooperation with Case Western Reserve University, University of South Carolina, Columbia University, University of Florida and other institutions. From the node color grouping, it can be seen that the University of Iowa, the University of Toronto, the University of Radford, and the University of Osaka, represented by the green nodes, have formed a strong cooperative sub-network; the yellow nodes such as the University of Kurumi and the University of Northland, as well as the University of Heidelberg and the University of Amsterdam in the red nodes also show a clear tendency of cluster cooperation. Among them, the University of Iowa and Osaka University (both green nodes) have established a wide and stable cooperative relationship.

3.5. Analysis of the most influential authors

Leading researchers in this field include Yamagishi S (62 articles), Stitt AW (55 articles), Takeuchi M (50 articles), and Matsui T (39 articles). Among them, Stitt AW leads in citation impact with 4,994 citations and an H‑index of 38, while Hammes HP, with 33 articles and 3,529 citations, ranks highest in citations per article, indicating particularly influential publications.

As visualized in the co‑citation network (Figure 3C, Figure 4A), authors are grouped into distinct thematic clusters. The yellow node, represented by Wiernsperger, Nicolas and Lagarde, Michel, focuses on the mechanism by which advanced glycation end-products induce pericyte apoptosis through oxidative stress and related metabolic pathways. Their work has identified novel biochemical targets, offering a fresh perspective for the treatment of DR. In the red node, authors such as Stitt, Alan W. and Nagai, Ryoji primarily investigate the role of retinal Müller glial cells in DR. The green node, including Endo, Tamao and Toda, Tatsushi, centers on the post‑translational modifications mediated by protein O‑linked mannose β1,2‑N‑acetylglucosaminyltransferase 1. The blue node, represented by Matsui, Takanori and Takeuchi, Masayoshi, explores the relationship between pigment epithelium‑derived factor and early‑stage DR.

Figure 4.

(A) Authors network visualization of co-citation analysis; (B) Journals network visualization of co-citation analysis; (C) Overlay visualization of citation analysis of Document, the weight was citation. (D) Network visualization of co-citation analysis of Reference, the weight was citation.

The timeline analysis in Figure 3D reveals shifts in research activity over time. Authors such as Gregory, Naina Sinha, Zhang, Yixin, Gornik, Olga, and van Hoek, Mandy show notable activity around 2024, reflecting recent research directions. In contrast, authors like Torelli, Silvia, Abbs, Stephen, and Straub, Volker were more active around 2010. Key findings from these authors include: Gubitosi‑Klug, Rose et al. reporting an association between type 1 diabetes and reduced bone mineral density, larger bone area, and impaired trabecular microstructure; Zhang, Yixin et al. identifying altered haptoglobin‑beta glycosylation as closely linked to DR, suggesting its potential for early diagnosis and screening; and Gornik, Olga et al. demonstrating the predictive potential of IgG N‑glycosylation in diabetic complications. Additionally, Godfrey, Caroline and Clement, Emma et al. described complex glycosylation patterns and discovered new glycan modifications in α‑dystroglycan, while Torelli, Silvia and Brown, Susan C. identified the first recessive mutation in DAG1 associated with a primary glycosylation disorder.

3.6. Analysis of Co-citation journals

The citation and clustering patterns of academic journals reveal the interdisciplinary foundations and evolving intellectual structure of research on glycated protein modification in ophthalmic diseases. As shown in the cocitation network (Figure 4B), journals form distinct thematic clusters that reflect both disciplinary focus and cross-domain integration. Journal of Biological Chemistry leads in total citations (10,136), underscoring its central role in publishing foundational biochemical and mechanistic studies. It is followed by Investigative Ophthalmology & Visual Science (9,591 citations), highlighting the strong ocular disease focus within the field, and Diabetes (8,420 citations), indicating the significant contribution of diabetes-related research. The cocitation network delineates three major journal clusters. The first cluster comprises Diabetes, Diabetologia, New England Journal of Medicine, Journal of Clinical Investigation, and Diabetes Care. This group bridges high-impact general medical journals (NEJM, JCI) with specialized diabetes publications, illustrating how the field connects broad clinical implications with specific metabolic pathology.

The second cluster consists of ophthalmic research journals, including Investigative Ophthalmology & Visual Science, Experimental Eye Research, Archives of Ophthalmology, Molecular Vision, and British Journal of Ophthalmology. This concentration emphasizes the disease-specific context and experimental models driving the applied research dimension. The third cluster, anchored by Journal of Biological Chemistry, includes Science, Proceedings of the National Academy of Sciences of the USA, Development, FEBS Letters, and The EMBO Journal. These journals represent the core basic science and molecular biology venues that supply the field with fundamental theories and advanced methodologies. The clustering of these journals is driven by strong similarities and overlaps in research scope, methodological approaches, technical paradigms, and mutual citation patterns. This structure not only maps the current knowledge integration and research hotspots but also serves as a strategic guide for researchers in identifying key literature, selecting appropriate publication targets, and recognizing influential cross-disciplinary connections within the field.

3.7. Analysis of highly cited studies

The top 10 frequently cited references are presented in Table 3. The co-citation analysis reveals core knowledge base driving research on glycosylated protein modification in ophthalmic diseases. Notably, the most frequently cited references are predominantly foundational studies in diabetes and metabolic disorders, rather than ophthalmology-specific papers. This pattern underscores that the research front in this ophthalmic subfield is deeply rooted in the mechanistic understanding of systemic diseases, particularly diabetic complications. Highly cited papers represent seminal works whose concepts, methods, or findings have been widely adopted and extended into subsequent ophthalmic research.

Table 3.

The Top 10 frequently cited references.

No.	Title	Journal	First author	Type	Year	Citations	Doi
1	Oxidative Stress and Diabetic Complications	Circulation Research	Giacco, F	Review	2010	3816	10.1161/CIRCRESAHA.110.223545
2	Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement	Endocrine Reviews	Diamanti-Kandarakis, E	Review	2009	3149	10.1210/er.2009-0002
3	Advanced glycation end-products: a review	Diabetologia	Singh, R	Review	2001	2021	10.1007/s001250051591
4	Muller cells in the healthy and diseased retina	Progress In Retinal and Eye Research	Bringmann, A	Review	2006	1395	10.1016/j.preteyeres.2006.05.003
5	Diabetic nephropathy: Diagnosis, prevention, and treatment	Diabetes Care	Gross, JL	Review	2005	1250	10.2337/diacare.28.1.164
6	Advanced glycation endproducts – role in pathology of diabetic complications	Diabetes Research and Clinical Practice	Ahmed, N	Review	2005	1146	10.1016/j.diabres.2004.09.004
7	Advanced glycation end products and diabetic complications	Korean Journal of Physiology & Pharmacology	Singh, VP	Review	2014	997	10.4196/kjpp.2014.18.1.1
8	Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss	Eye And Vision	Lee, R	Review	2015	985	10.1186/s40662-015-0026-2
9	Drusen proteome analysis: An approach to the etiology of age-related macular degeneration	Proceedings of the National Academy of Sciences of the United States of America	Crabb, JW.	Article	2002	980	10.1073/pnas.222551899
10	Current concepts in the pathogenesis of age-related macular degeneration	Archives of Ophthalmology	Zarbin, MA	Review	2004	827	10.1001/archopht.122.4.598

The most cited article is “Oxidative Stress and Diabetic Complications” (3,816 citations). It established the critical role of OS in diabetic microvascular damage, demonstrating that overexpression of superoxide dismutase could prevent DR in models. This work provides a fundamental mechanistic link directly applicable to understanding DR pathogenesis. The second most cited article, “Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement” (3,149 citations), broadens the perspective to environmental influences on metabolic pathways. While not focused on the eye, its comprehensive review of disruption mechanisms involving nuclear receptors (e.g., PPARγ) and enzymatic systems offers essential background for investigating how environmental factors might influence glycosylation processes relevant to ocular disease. The prominence of these foundational diabetes and biochemistry references in an ophthalmic co-citation core clearly indicates that research on glycosylated protein modification in the eye is inherently interdisciplinary. It relies heavily on the theoretical frameworks and discoveries from parent fields, applying them to elucidate specific ophthalmic pathologies, with DR being a primary driver of this research nexus.

The prominence of these foundational diabetes and biochemistry references within an ophthalmic co-citation core reflects the intrinsic interdisciplinary nature of this research domain. The molecular mechanisms underlying glycation-including AGE formation, oxidative stress, mitochondrial dysfunction, and inflammatory signaling-were originally elucidated in systemic metabolic disease models [19–21]. Ophthalmic research, particularly in DR, has subsequently adopted and refined these mechanistic paradigms to explain retinal microvascular injury, neurovascular unit disruption, and blood–retinal barrier breakdown [22,23]. Therefore, the dominance of metabolism-oriented literature in the highly cited and co-cited corpus does not indicate a scarcity of ophthalmology-specific research. Rather, it illustrates the translational trajectory from systemic metabolic pathophysiology to ocular-specific disease mechanisms. In this context, DR serves as the central research nexus linking endocrinology, molecular biology, and ophthalmology, positioning the eye as both a target organ of systemic metabolic dysfunction and a model for studying glycosylation-related microvascular pathology.

3.8. Co-citation analysis of cited references

Co-citation analysis measures how frequently two documents are cited together by subsequent research. A higher co-citation strength indicates stronger semantic relevance between the publications in terms of topic, theory, or methodology, and helps reveal the core knowledge structure of a field. Table 4 lists the ten most frequently co-cited references in this domain, among which the top three constitute foundational pillars for understanding the evolution of research on diabetes and its ocular complications.

Table 4.

The top 10 co-citation references.

No.	Title	Journal	First author	Type	Year	Citations	Doi
1	The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes-mellitus	New England Journal of Medicine	Reichard, P	Article	1993	19,341	10.1056/NEJM199307293290502
2	Biochemistry and molecular cell biology of diabetic complications	Nature	Brownlee, M	Review	2001	7902	10.1038/414813a
3	Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (ukpds 33)	Lancet	Turner, RC	Article	1998	15018	10.1016/S0140-6736(98)07019-6
4	Vascular endothelial growth-factor in ocular fluid of patients with diabetic-retinopathy and other retinal disorders	New England Journal of Medicine	Aiello, LP	Article	1994	3125	10.1056/NEJM199412013312203
5	Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, pomgnt1	Developmental Cell	Yoshida, A	Article	2001	546	10.1016/s1534-5807(01)00070-3
6	Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy	Proceedings of the National Academy of Sciences of the United States of America	Hammes HP	Article	1991	462	10.1073/pnas.88.24.11555
7	Advanced glycation end-products: a review	Diabetologia	Singh, R	Review	2001	2022	10.1007/s001250051591
8	Mutations in the o-mannosyltransferase gene pomt1 give rise to the severe neuronal migration disorder walker-warburg syndrome	American Journal of Human Genetics	Beltran-Valero de Bernabe, D	Article	2002	507	10.1086/342975
9	Normalizing mitochondrial superoxide production blocks three pathways of hyperglycemic damage	Nature	Nishikawa, T	Article	2000	3445	10.1038/35008121
10	The pathobiology of diabetic complications – a unifying mechanism	Diabetes	Brownlee, M	Article	2005	3910	10.2337/diabetes.54.6.1615

The most cited reference, “The Effect of Long-Term Intensified Insulin-Treatment on The Development of Microvascular Complications of Diabetes-Mellitus,” is a landmark clinical study. By systematically analyzing the relationship between blood glucose control and microvascular complications in patients with insulin-dependent diabetes, it provided high-level evidence for the first time, demonstrating that long-term intensive insulin therapy can significantly delay the onset and progression of microvascular complications such as DR and nephropathy. This finding fundamentally established the central role of strict glycemic control in diabetes management.

The second most co-cited work, “Biochemistry and Molecular Cell Biology of Diabetic Complications,” is a highly influential review. It systematically proposed and elaborated a unifying mechanism theory for hyperglycemia-induced complications, identifying the overproduction of reactive oxygen species by the mitochondrial electron transport chain as the common initiating pathway. This article not only clarified that diabetes-specific microvascular diseases are the main causes of blindness and renal failure but also revealed the deeper molecular and cellular basis for how diabetes accelerates atherosclerosis and increases cardiovascular risk, providing a key theoretical framework for subsequent targeted therapeutic research.

The third key reference, “Intensive Blood-Glucose Control with Sulphonylureas or Insulin Compared with Conventional Treatment and Risk of Complications in Patients with Type 2 Diabetes,” shifted the focus to type 2 diabetes. This important comparative clinical trial yielded a conclusion of great practical significance: although intensive glucose-lowering therapy significantly reduces the risk of microvascular complications, it has limited effect on preventing macrovascular events such as myocardial infarction and stroke. This finding prompted the academic community to reevaluate the limitations of glycemic management strategies and encouraged a shift toward more comprehensive risk-control models.

In summary, these three foundational publications are closely linked within the co-citation network. Together, they clearly outline the field’s complete “clinical–basic–clinical” knowledge cycle: from establishing the importance of glycemic control, to elucidating the underlying unifying mechanism of oxidative stress, and further validating these insights across different types of diabetes and spectra of complications through clinical research. This intellectual progression continues to guide the direction of research in the field.

3.9. Analysis of Co-occurrence keywords

The keyword co-occurrence network visually reveals high-frequency terms and their interrelationships within a research field. A higher co-occurrence frequency indicates closer thematic links, enabling the identification of current research hotspots and core topics. Analysis of this network aids in understanding the knowledge structure and its evolution. It is important to note that the search strategy and subsequent analysis encompass both enzymatic protein glycosylation and non-enzymatic protein glycation. These two distinct yet interconnected biochemical processes are central to the pathobiology of many ophthalmic diseases, with DR serving as the predominant and most researched model system. Consequently, the keyword clusters naturally reflect this interdisciplinary nexus, integrating pathways fundamental to diabetes complications with broader protein modification biology. The top 10 keywords within the 4 identified clusters are listed in Table 5.

Table 5.

The top 10 keywords in the 4 clusters.

Cluster 1	Occurrences	Total link strength	Cluster 2	Occurrences	Total link strength
Glycation end-products	937	5230	expression	456	2280
Oxidative stress	633	3954	protein	161	740
Diabetic retinopathy	436	2983	identification	158	618
Endothelial growth-factor	358	2239	alpha-dystroglycan	150	826
Receptor	216	1333	gene	144	569
Cells	209	1080	mutations	116	524
Inflammation	204	1369	walker-warburg-syndrome	111	646
Activation	199	1177	congenital muscular-dystrophy	92	527
Advanced glycation end products	169	1176	extracellular-matrix	80	432
Apoptosis	155	1024	retinoic acid	80	243
Cluster 3	Occurrences	Total link strength	Cluster 4	Occurrences	Total link strength
Diabetes	276	1779	glycosylation	507	1847
Glycation	274	1534	retinopathy	382	2516
In-vitro	187	1126	complications	278	1823
Proteins	160	865	diabetes mellitus	165	1008
Age	132	852	mellitus	165	974
Glucose	131	872	nephropathy	162	1084
End-products	120	733	disease	161	960
Maillard reaction	119	689	retina	129	815
Cataract	107	624	risk	101	624
Aldose reductase	106	711	hyperglycemia	96	665

Cluster 1 represented by red nodes is related to the pathogenesis of DR. This cluster directly encapsulates the core pathological pathways in DR. It highlights the central research focus on how AGEs, via receptors like RAGE and through induction of OS, drive cellular damage, inflammation, and aberrant angiogenesis mediated by vascular endothelial growth factor. This cluster confirms DR as the primary disease context for studying glycation/glycosylation in the eye. The green node is cluster 2, which mainly focuses on the content of molecular and genetic basis. This cluster represents research at the molecular level, focusing on gene and protein expression profiling, mutation identification, and specific targets like alpha-dystroglycan-a key protein whose function is regulated by glycosylation. It underscores the translational direction of the field, aiming to identify genetic markers and molecular mechanisms underlying glycosylation-related pathologies.

The blue node is cluster 3, which is mainly related to basic biochemical and experimental research. This cluster centers on the basic science foundation, encompassing in vitro studies that investigate the glycation process itself, its impact on protein structure/function under high glucose conditions, and its contribution to aging and diabetic complications. It provides the mechanistic bridge between systemic diabetes and ocular pathology. The yellow node is cluster 4, which mainly focuses on the core themes of diabetic complications and post-translational modification. This cluster aggregates the broadest thematic terms, explicitly linking the overarching concepts of glycosylation, retinopathy, and diabetic complications. The strong co-occurrence affirms that the study of PTMs, particularly glycosylation/glycation, is considered a core axis in understanding and addressing these complications. In the network map (Figure 5A), nodes represent keywords and links represent co-occurrence. Larger node size indicates higher frequency, denoting a major research hotspot. This visualization assists researchers in quickly identifying core themes and understanding the structural dynamics of the field, which is fundamentally oriented around diabetic eye disease as a primary model for exploring glycosylation and glycation biology.

Figure 5.

(A) Network visualization map of all keywords co-occurrence; (B) Visualization map of the top 25 keywords with the strongest citation bursts. The strongest citation burst means that a variable changes greatly in a short period. Red bars indicate the duration of the burst.

3.10. Analysis of keywords with citation burst

The keyword burst map serves as an effective tool for rapidly identifying terms that experience a sudden increase in frequency within a specific time, reflecting emerging research frontiers and shifting hotspots in a given field. By visualizing the burst strength, onset year, and duration of keywords, this analysis helps researchers trace the evolution of scholarly focus and anticipate potential future directions. In the map, red segments indicate keywords currently in a phase of rapid growth, representing active research fronts, while blue segments denote keywords that are in decline or have stabilized. The length of the burst line corresponds to the duration of the keyword’s prominence; longer lines generally signify sustained influence within literature.

As clearly shown in Figure 5B, early bursts such as “advanced glycosylation” (Strength = 17.22), “diabetes mellitus” (Strength = 16.51), “non-enzymatic glycosylation” (Strength = 11.9), and “complications” (Strength = 11.9) emerged around 1995, aligning with foundational concepts and initial research directions in the field. Subsequently, keywords like “glycosylation end products” (Strength = 27.65, 1996–2005) and “protein kinase c” (Strength = 20.63, 1998–2009) exhibited higher burst strengths, indicating intense research activity over a concentrated period. More recent bursts include “insulin resistance” (Strength = 16.4, appearing in 2015), “inflammation” (Strength = 17.06, 2019), and “risk” (Strength = 12.62, 2020), with continued prominence projected into 2025. These terms likely correspond to sustained or emerging research priorities and frontier topics. Overall, the keyword burst map enables researchers to quickly identify evolving hotspots, track thematic shifts, and gain insight into the latest trends within the research landscape.

4. Discussion

4.1. Analysis of network map results

The comprehensive analysis of annual publication volume, subject distribution, international collaboration, author co-occurrence, journal co-citation, and keyword networks depicts the historical trajectory and internal knowledge structure of this field.

The literature growth trend (Figure 1B) and the evolution of high-impact authors (Figure 3D) indicate sustained research momentum. The research frontier has shifted from traditional diabetic complication mechanisms centered on AGEs and oxidative stress to more refined molecular glycosylation processes and clinically oriented topics such as risk assessment and biomarkers (Figure 5B). However, the keyword co-occurrence map (Figure 5A) demonstrates that current hotspots remain highly concentrated in the posterior segment, particularly DR. The AGE-RAGE-VEGF-OS axis has dominated the research landscape for two decades, reflecting both the depth and relative thematic concentration of the field.

The interdisciplinary network (Table 1) and journal co-citation clustering (Figure 4B) highlight the integration of biochemistry, molecular biology, endocrinology, and ophthalmology, which has been particularly successful in DR research. However, this paradigm has not been fully extended to other ophthalmic subspecialties. Glycemic signals related to ocular surface diseases such as dry eye and infectious keratitis remain comparatively weak in the keyword network, suggesting a potential expansion area.

Glycosylation exhibits clear region-specific characteristics within the eye. At the ocular surface, glycosylation regulates mucin stability and epithelial glycocalyx integrity, maintaining tear film homeostasis and barrier function; disruption may predispose to inflammatory and infectious surface disorders. In contrast, in the posterior segment-especially the retina-glycosylation and glycation are closely linked to microvascular dysfunction, oxidative stress, complement activation, and blood-retinal barrier breakdown, particularly in DR. Functional roles also differ: ocular surface glycans primarily mediate lubrication and immune defense, whereas retinal glycan modifications influence receptor signaling, extracellular matrix remodeling, and angiogenic regulation.

Accordingly, research strategies diverge between compartments. Ocular surface studies emphasize tear proteomics and glycocalyx characterization, whereas posterior segment research focuses on molecular pathways, AGE-RAGE signaling, and diabetic vascular models. These differences indicate that glycosylation in ophthalmology is compartment-specific rather than uniform. The international cooperation map (Figure 2) shows Europe and North America as leading contributors, with active participation from East Asia and emerging potential in other regions. Expanding collaborative networks may facilitate exploration of underdeveloped areas such as ocular surface glycobiology. In summary, glycosylation research in ophthalmology has established a solid knowledge base centered on DR. Future development should extend mature interdisciplinary approaches to clinically significant yet underexplored domains, particularly ocular surface diseases.

The predominance of DR in the bibliometric landscape has broader implications for the overall development of ophthalmological research. On the positive side, DR has functioned as a representative microvascular model of systemic metabolic disease, facilitating interdisciplinary integration between endocrinology, molecular biology, vascular biology, and ophthalmology. This concentration has accelerated mechanistic discoveries-particularly regarding the AGE-RAGE-oxidative stress axis-and promoted translational progress in biomarker identification and targeted therapeutic strategies [24,25]. However, the strong focus on DR also indicates a relative imbalance in thematic distribution within ophthalmology. While DR research has achieved methodological maturity and conceptual depth, other clinically significant areas-such as ocular surface disorders, non-diabetic retinal diseases, and certain glaucoma subtypes-remain comparatively underrepresented in glycosylation research [26–28]. Therefore, future research should build upon the established DR-centered paradigm while actively expanding into underexplored domains, thereby fostering a more balanced and integrative advancement of ophthalmological glycobiology.

4.2. The mechanism of glycosylation and glycation in ophthalmic diseases

Keyword co-occurrence and clustering map clearly show that the research on the mechanism of sugar modification in ophthalmic diseases mainly focuses on DR, AMD and glaucoma, and forms a distinct knowledge framework with specific molecular pathways as the core. In the research cluster of DR, the keyword map highlights the close association of terms such as AGEs、 receptor、OS、inflammation [29]. In high glucose environment, the accumulation of AGES and its combination with RAGE on the cell surface are the key initial events driving the downstream pathological process [30,31].

The activation of this pathway, on the one hand, causes OS, leading to mitochondrial dysfunction and apoptosis of retinal cells [32,33]. on the other hand, it activates inflammatory signaling pathways such as Nuclear Factor Kappa B, promotes the release of IL-1β, TNF-α and other factors, and aggravates retinal damage [34,35]. In addition, the effect of modification on vascular endothelial function and blood-retinal barrier integrity is also the focus of the research cluster [36–38]. It is worth noting that such multiple pathological mechanisms driven by glycosylation modification may partially explain why, for complex diseases such as PDR with DME, combined vitrectomy and anti-VEGF multimodal therapy can bring better long-term visual function and anatomical structure benefits than single therapy [39].

For AMD, bibliometric analysis reveals its different research focus from DR. More functional terms such as retinal pigment epithelium、complement system、phagocytosis have been studied [40,41]. This reflects the current research aimed at elucidating how glycosylation modification affects the functional homeostasis of RPE cells, such as phagocytosis of photoreceptor outer segment disk membrane and how it is involved in the formation of AMD characteristic deposits. The sugar components in these abnormal sediments may play an important role in the pathogenesis of AMD by activating the complement system and amplifying the local inflammatory response [42]. Compared with the DR field, AMD’s sugar modification research map shows a closer connection with innate immunity and cell-specific functions. In glaucoma-related studies, the keyword network suggests that the focus of research is on retinal ganglion cells、apoptosis and OS [43,44]. Recent genetic studies have shown that there is a weak causal association between genetic susceptibility to primary open angle glaucoma and the risk of schizophrenia [45].

Glycosylation and glycosylation are involved in the pathological process of various ophthalmic diseases by a affecting mechanisms like oxidative stress, inflammatory response, cell-specific function and barrier integrity. Different disease domains present different focus points on the knowledge map: DR research focuses on a clear metabolism-receptor-signal axis, AMD research focuses on the interaction between cell function and immunity, and glaucoma focuses on the damage pathway of nerve cells. This model not only confirms the known core pathological mechanism, but also enlightens us that while consolidating the existing main line, future research should draw on the frontier paradigm of signal integration in system neuroscience to explore how pathological glycosylation modification, as a continuous disorder signal, destroys the normal communication network between different cell types in the retina and even between the eye and the whole body system, so as to reveal its pathogenic essence at a more integrated level [46]. At the same time, we should also strengthen the exploration of relatively weak fields such as dry eye and cataract and deeply explore the intersection and difference between different disease-specific mechanisms.

4.3. The potential of glycosylation and glycation in the diagnosis of ophthalmic diseases

The in-depth exploration of the mechanism of protein glycosylation and glycosylation modification not only provides a window for revealing the nature of ophthalmic diseases but also leads to the discovery of new diagnostic markers. The research in this field has gradually shifted from extensive mechanism exploration to diagnostic applications with clear clinical transformation potential, especially in DR and AMD, forming a marker research cluster with specific biomolecules as the core.

In the DR study, the keywords and co-citation network highlighted the strong correlation of terms such as biomarkers、immunoglobulin G、advanced glycation end products. It was found that the glycosylation pattern of disease-specific IgG in the serum of DR patients was significantly different from that of non-DR diabetic patients, and the pattern evolved dynamically with disease progression, indicating that the ratio of specific glycopeptides can be used as a potential serological marker for disease staging [47]. Further studies have pointed out that the increase of globin β-subbasal fucosylation and the decrease of sialylation are expected to be the early diagnostic indicators of DR in the background period [48,49]. Together, these findings constitute a subfield of DR diagnostic research with ‘humoral glycoprotein’ changes as the core. At the same time, the strong ‘AGEs’ cluster in the map points to another more mature marker pathway: the level of specific AGEs such as carboxymethyl lysine in serum has been repeatedly confirmed to be positively correlated with the severity of DR, and established its status as a biomarker of pathological relevance [50].

In the field of AMD research, although the mechanism research cluster is more associated with complement and inflammation, the direction of diagnostic exploration has emerged. The co-occurrence of plasma、glycosylation、AMD in the bibliometric map of the literature reflects that the study is trying to correlate the changes of specific glycoprotein levels in patients ‘ serum with disease stage and visual impairment degree, so as to find the basis for early intervention [51,52]. The formation of glycated fibrinogen by D-ribose-mediated fibrinogen glycosylation further expands the list of DR markers based on glycated proteins [53]. Congenital glycosylation abnormality is a kind of hereditary disease caused by defects in the glycosylation process, and most patients are accompanied by eye abnormalities. Important steroid 5a-reductase type 3 congenital glycosylation defects. For example, in steroid 5alpha-reductase type 3 deficiency patients, early retinal dystrophy and optic nerve hypoplasia are the main diagnostic features, and studies have found that they have unique PTMs patterns. The key clinical diagnostic feature of steroid 5alpha-reductase type 3 deficiency is the early onset of ophthalmic problems in patients with multi-system diseases, and the symptoms change over time [54,55]. Changes in the level of PTMs can also be used to predict the prognosis of the disease. For example, studies have found that elevated serum AGES levels in patients with DR are associated with decreased vision and increased risk of disease progression. In addition, in AMD, patients with abnormal PTMs may face a higher risk of visual loss, which provides an important basis for the prognosis evaluation of the disease [56].

The core contribution of highly cited classical literature in bibliometric analysis, such as the experimental study of diabetes control and complications, is to push glycosylation markers from phenomenon association to causal argument. In this study, it was confirmed by liquid chromatography-mass spectrometry that the levels of 11 plasma protein-bound AGEs were closely related to the progression of microvascular complications in type 1 diabetes [57].

The emergence of keywords such as mass spectrometry and lectin chip in the spectrum indicates that the progress of detection technology is the key driving force for the development of this field [58–61]. The extensiveness, relative stability and detectability of glycosylation/glycosylation modification endow it with unique advantages as a biomarker. However, cluster analysis also indirectly reveals the challenge: the complexity of the glycosylation process is influenced by genetic, environmental and other factors, resulting in significant differences between individuals [62–65]. This increases the difficulty of markers from discovery to extensive clinical verification and standardization and also suggests that future research needs to pay more attention to population heterogeneity and large sample verification. Based on the bibliometric pattern, there is a clear path for future research on diagnostic markers. Firstly, large-scale, prospective cohort studies should be carried out on the basis of the existing marker clusters of DR and AMD to strictly verify their diagnostic specificity, sensitivity and prognostic value. Secondly, we should pay attention to the relatively weak disease areas in the map, such as glaucoma and dry eye, and explore their unique sugar modification markers. Finally, by integrating multi-omics data and using artificial intelligence to analyze complex sugar pattern changes, it is expected to find more powerful combined markers for diagnosis and prognosis prediction and finally realize the leap from basic research to clinical application.

4.4. Application of glycosylation and glycation in the treatment of ophthalmic diseases

The map analysis clearly shows that AGEs and RAGE are in the hub position in the co-occurrence network of DR, AMD and even cataract, which determines that the current treatment strategy with the most transformation prospects mainly focuses on blocking this pathological axis. Studies have shown that AGEs drive downstream OS, inflammatory cascade and vascular endothelial dysfunction by binding to its receptor RAGE in DR, which is a key link leading to retinal injury and neovascularization [66–68]. In response to this pathway, strategies including AGEs formation inhibitors, RAGE antagonists or soluble RAGE, and AGE breaker designed to remove accumulated AGEs have emerged. These interventions have shown the potential to reduce DR pathological changes and protect the blood-retinal barrier in preclinical models [69,70]. Similarly, in AMD, the AGEs-RAGE axis is also considered to be associated with RPE dysfunction and choroidal neovascularization, making it a potential therapeutic target [64,71]. In addition to the glycosylation pathway, interventions targeting specific enzymatic glycosylation processes are also emerging. Studies on specific glycosyltransferases or glycosidases mentioned in the map suggest the possibility of correcting abnormal glycosylation patterns by regulating enzyme activity. For example, in glaucoma studies, abnormalities in the function of trabecular meshwork cells may be associated with an imbalance in local glycosylation homeostasis, suggesting that restoring their normal glycosylation environment may be a new idea for regulating aqueous outflow and reducing intraocular pressure [72]. Although these studies are still in their infancy, they have opened the way for the development of more accurate glycosylation targeted therapies beyond the AGES-RAGE axis.

Based on the knowledge pattern presented by bibliometrics, the development of future treatment strategies should follow the following paths: deepening the verification of core targets, promoting the transformation of its inhibitors or blockers from preclinical research to early clinical trials for the established AGES-RAGE axis, and strictly evaluating its efficacy and safety in humans. Explore new mechanism targets, use keyword co-occurrence and cluster analysis to identify glycosyltransferases, glycosidases or specific glycoform structures that are strongly related to the disease but have not been fully explored in the map, and use them as candidate therapeutic targets for functional verification. Develop precise intervention strategies, combined with disease subtype-specific sugar modification maps, to design targeted delivery systems with cell or tissue selectivity to improve efficacy and reduce systemic side effects. To explore the potential of combined therapy, because sugar modification is intertwined with OS, inflammation and other pathways, future research should consider combining sugar-modified targeted drugs with existing anti-VEGF, anti-inflammatory or neuroprotective therapies in order to produce synergistic effects.

Glycosylation and glycosylation modification show a clear logic from mechanism’ understanding to targeted intervention in the treatment of ophthalmic diseases. The bibliometric map not only confirms that the AGES-RAGE axis is the most popular therapeutic target cluster but also reveals the germination of emerging directions such as enzymatic glycosylation regulation. Although direct therapeutic transformation research is still growing, by systematically mining map information, verifying core targets and exploring innovative strategies, targeted sugar modification is expected to become an important part of comprehensive treatment of ophthalmic diseases in the future, achieving a leap from delaying disease progression to functional repair.

Nevertheless, some limitations should be acknowledged. First, due to our inclusion criteria, only English-language publications were included, which may have resulted in the exclusion of relevant studies published in other languages. Second, articles published in 2025 were not incorporated into the present analysis; therefore, the most recent research developments and emerging keywords may not be fully reflected. In addition, although the Web of Science Core Collection provides high-quality and standardized bibliographic data, certain clinically oriented or regional ophthalmology journals may have limited or delayed indexing within this database. Consequently, some relevant clinical studies or region-specific research outputs may not have been fully captured, potentially leading to underrepresentation of specific geographic regions or subspecialty domains. Future bibliometric analyses may benefit from integrating additional databases, such as Scopus or PubMed, to provide a more comprehensive and balanced overview of glycosylation and glycation research in ophthalmology.

5. Conclusion

Taken together, the present study conducted a bibliometric and visual analysis of the literature on the application of glycosylation and glycation to ophthalmic diseases published from 1997 to 2024. After a strict evaluation of the existing literature, we selected 3221 related literatures as the analysis object. Bibliometric analysis results show that glycosylation and glycation is an important research field with rapid development. In this field, the United States possesses significant academic influence. Keyword overlay visualization and keyword citation analysis showed that the research hotspots of glycosylation and glycation may include “glycation end-products”, “oxidative stress”, “expression”, “protein”, “diabetes”, “glycation”, “glycosylation”, “retinopathy”. Future research can further explore the specific mechanism of glycosylation and glycation in ophthalmic diseases, develop new diagnostic markers and therapeutic targets for glycosylation and glycation and provide more effective means for clinical treatment of ophthalmic diseases.

Funding Statement

This work was finically supported by the Key Research and Development Program of Shaanxi Province (No. 2024SF-YBXM-333, No. 2024SF-YBXM-337) and the Scientific Research Project of the Xi’an Health Commission (No. 2024ms04).

Author contributions

Hongsong Li: Conceptualization, Methodology, Data curation, Formal analysis, Writing – original draft, Funding acquisition. Jing Xu: Methodology, Investigation, Formal analysis, Visualization. Jiahui Wang: Methodology, Software. Lina Cheng: Data curation, Formal analysis, Validation, Visualization. Jingjing Fan: Supervision, Writing – review and editing, Funding acquisition, Formal analysis.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Ethical disclosure statement

Ethical approval was not required for this bibliometric analysis as it was based on publicly available literature data.

Data availability statement

Data will be made available on request.