{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:53:40Z","timestamp":1785772420824,"version":"3.56.0"},"reference-count":102,"publisher":"IMR Press","issue":"5","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Diabetic retinopathy (DR) is increasingly recognized as a complex neurovascular degenerative disorder driven by intertwined immune and metabolic disturbances within the retinal microenvironment. Chronic hyperglycemia induces metabolic stress, mitochondrial dysfunction, and oxidative imbalance, which, in turn, activate innate and adaptive immune pathways. Key mechanisms\u2014including complement dysregulation, microglial activation, leukostasis, cytokine and chemokine signaling, and advanced glycation end-product\u2013mediated inflammation\u2014contribute to endothelial injury, barrier breakdown, and progressive neuronal loss. Parallel alterations in lipid metabolism, amino acid utilization, and mitochondrial bioenergetics further amplify inflammatory cascades and shape the retinal immune landscape. This review synthesizes current evidence on how immune-metabolic crosstalk orchestrates early and late stages of DR, integrating findings from transcriptomic, proteomic, metabolomic, and epigenetic studies. We examine core signaling hubs that couple metabolic dysfunction to inflammatory amplification, including complement components, the advanced glycation end product (AGE)\u2013receptor for AGE (RAGE) pathway, cytokine networks, and immune response regulation. Adopting a systems biology perspective, we highlight how convergent mechanisms can unify vascular, neuronal, and glial pathology under a shared framework of immune-metabolic imbalance. An extensive literature search was conducted (PubMed, accessed December 2025). By positioning DR as a model of inflammatory retinal degeneration, this review outlines a conceptual foundation for network-based diagnostics and therapeutics. Understanding the dynamic interactions among immune signaling, metabolic stress, and neurovascular instability may inform future strategies to restore retinal homeostasis and prevent vision-threatening disease progression.<\/jats:p>","DOI":"10.31083\/fbl49588","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T07:25:36Z","timestamp":1780125936000},"source":"Crossref","is-referenced-by-count":2,"title":["Immune-Metabolic Interactions in the Degenerative Retina: A Systems Biology Approach Based on Diabetic Retinopathy"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6807-9455","authenticated-orcid":true,"given":"Francesco","family":"Cappellani","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, Piazza dell\u2019Universit\u00e0, 94100 Enna, Italy"},{"name":"Mediterranean Foundation \u201cG.B. Morgagni\u201d, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8424-0068","authenticated-orcid":true,"given":"Caterina","family":"Gagliano","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, Piazza dell\u2019Universit\u00e0, 94100 Enna, Italy"},{"name":"Mediterranean Foundation \u201cG.B. Morgagni\u201d, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1829-9288","authenticated-orcid":true,"given":"Cosimo","family":"Mazzotta","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, Piazza dell\u2019Universit\u00e0, 94100 Enna, Italy"},{"name":"Mediterranean Foundation \u201cG.B. Morgagni\u201d, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7938-876X","authenticated-orcid":true,"given":"Fabiana","family":"D\u2019Esposito","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, Piazza dell\u2019Universit\u00e0, 94100 Enna, Italy"},{"name":"Imperial College Ophthalmic Research Group (ICORG) Unit, Imperial College, NW1 5QH London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1051-876X","authenticated-orcid":true,"given":"Alessandro","family":"Avitabile","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0059-5253","authenticated-orcid":true,"given":"Giuseppe","family":"Gagliano","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7197-7765","authenticated-orcid":true,"given":"Daniele","family":"Tognetto","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34129 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0999-5545","authenticated-orcid":true,"given":"Marco","family":"Zeppieri","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34129 Trieste, Italy"},{"name":"Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005; 54: 1615\u20131625.","DOI":"10.2337\/diabetes.54.6.1615"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Mesquida M, Drawnel F, Fauser S. The role of inflammation in diabetic eye disease. Seminars in Immunopathology. 2019; 41: 427\u2013445.","DOI":"10.1007\/s00281-019-00750-7"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. The New England Journal of Medicine. 2012; 366: 1227\u20131239.","DOI":"10.1056\/NEJMra1005073"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. 2017; 2: e93751.","DOI":"10.1172\/jci.insight.93751"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Srinivasan S, Sivaprasad S, Rajalakshmi R, Anjana RM, Malik RA, Kulothungan V, et al. Early retinal functional alteration in relation to diabetes duration in patients with type 2 diabetes without diabetic retinopathy. Scientific Reports. 2022; 12: 11422.","DOI":"10.1038\/s41598-022-15425-x"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Kang Q, Yang C. Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biology. 2020; 37: 101799.","DOI":"10.1016\/j.redox.2020.101799"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Tien T, Zhang J, Muto T, Kim D, Sarthy VP, Roy S. High Glucose Induces Mitochondrial Dysfunction in Retinal M\u00fcller Cells: Implications for Diabetic Retinopathy. Investigative Ophthalmology & Visual Science. 2017; 58: 2915\u20132921.","DOI":"10.1167\/iovs.16-21355"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017; 542: 177\u2013185.","DOI":"10.1038\/nature21363"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Joyal JS, Gantner ML, Smith LEH. Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism. Progress in Retinal and Eye Research. 2018; 64: 131\u2013156.","DOI":"10.1016\/j.preteyeres.2017.11.002"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Altmann C, Schmidt MHH. The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration. International Journal of Molecular Sciences. 2018; 19: 110.","DOI":"10.3390\/ijms19010110"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Sim\u00f3 R, Stitt AW, Gardner TW. Neurodegeneration in diabetic retinopathy: does it really matter? Diabetologia. 2018; 61: 1902\u20131912.","DOI":"10.1007\/s00125-018-4692-1"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Kinuthia UM, Wolf A, Langmann T. Microglia and Inflammatory Responses in Diabetic Retinopathy. Frontiers in Immunology. 2020; 11: 564077.","DOI":"10.3389\/fimmu.2020.564077"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Zong H, Ward M, Stitt AW. AGEs, RAGE, and diabetic retinopathy. Current Diabetes Reports. 2011; 11: 244\u2013252.","DOI":"10.1007\/s11892-011-0198-7"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Whitehead M, Wickremasinghe S, Osborne A, Van Wijngaarden P, Martin KR. Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies. Expert Opinion on Biological Therapy. 2018; 18: 1257\u20131270.","DOI":"10.1080\/14712598.2018.1545836"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Rodr\u00edguez ML, Mill\u00e1n I, Ortega \u00c1L. Cellular targets in diabetic retinopathy therapy. World Journal of Diabetes. 2021; 12: 1442\u20131462.","DOI":"10.4239\/wjd.v12.i9.1442"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Cappellani F, Regillo CD, Haller JA, Gagliano C, Pulido JS. Exploring the Associated Genetic Causes of Diabetic Retinopathy as a Model of Inflammation in Retinal Diseases. International Journal of Molecular Sciences. 2024; 25: 5456.","DOI":"10.3390\/ijms25105456"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Li X, Dong X, Zhang W, Shi Z, Liu Z, Sa Y, et al. Multi-omics in exploring the pathophysiology of diabetic retinopathy. Frontiers in Cell and Developmental Biology. 2024; 12: 1500474.","DOI":"10.3389\/fcell.2024.1500474"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Youngblood H, Robinson R, Sharma A, Sharma S. Proteomic Biomarkers of Retinal Inflammation in Diabetic Retinopathy. 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Oxidative Medicine and Cellular Longevity. 2018; 2018: 3420187.","DOI":"10.1155\/2018\/3420187"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Yue T, Shi Y, Luo S, Weng J, Wu Y, Zheng X. The role of inflammation in immune system of diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Frontiers in Immunology. 2022; 13: 1055087.","DOI":"10.3389\/fimmu.2022.1055087"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Kowluru RA, Mishra M. Oxidative stress, mitochondrial damage and diabetic retinopathy. Biochimica et Biophysica Acta. 2015; 1852: 2474\u20132483.","DOI":"10.1016\/j.bbadis.2015.08.001"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Li B, Hussain W, Jiang ZL, Wang JY, Hussain S, Yasoob TB, et al. Nuclear proteins and diabetic retinopathy: a review. Biomedical Engineering Online. 2024; 23: 62.  [Erratum in: Biomed Eng Online. 2024 Oct 10;23(1):99. doi: 10.1186\/s12938-024-01293-1. 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Epigenetics and Mitochondrial Stability in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy. Scientific Reports. 2020; 10: 6655.","DOI":"10.1038\/s41598-020-63527-1"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Pan WW, Lin F, Fort PE. The innate immune system in diabetic retinopathy. Progress in Retinal and Eye Research. 2021; 84: 100940.","DOI":"10.1016\/j.preteyeres.2021.100940"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Shahulhameed S, Vishwakarma S, Chhablani J, Tyagi M, Pappuru RR, Jakati S, et al. A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy. Frontiers in Immunology. 2020; 11: 154.","DOI":"10.3389\/fimmu.2020.00154"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Yang Y, Jiang G, Huang R, Liu Y, Chang X, Fu S. Targeting the NLRP3 inflammasome in diabetic retinopathy: From pathogenesis to therapeutic strategies. Biochemical Pharmacology. 2023; 212: 115569.","DOI":"10.1016\/j.bcp.2023.115569"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Bianco L, Arrigo A, Aragona E, Antropoli A, Berni A, Saladino A, et al. Neuroinflammation and neurodegeneration in diabetic retinopathy. Frontiers in Aging Neuroscience. 2022; 14: 937999.","DOI":"10.3389\/fnagi.2022.937999"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Rodriguez D, Church KA, Pietramale AN, Cardona SM, Vanegas D, Rorex C, et al. Fractalkine isoforms differentially regulate microglia-mediated inflammation and enhance visual function in the diabetic retina. Journal of Neuroinflammation. 2024; 21: 42.","DOI":"10.1186\/s12974-023-02983-8"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Park YG, Lee JY, Kim C, Park YH. Early Microglial Changes Associated with Diabetic Retinopathy in Rats with Streptozotocin-Induced Diabetes. Journal of Diabetes Research. 2021; 2021: 4920937.","DOI":"10.1155\/2021\/4920937"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Wang Y, Yang X, Zhang Y, Hong L, Xie Z, Jiang W, et al. Single-cell RNA sequencing reveals roles of unique retinal microglia types in early diabetic retinopathy. Diabetology & Metabolic Syndrome. 2024; 16: 49.","DOI":"10.1186\/s13098-024-01282-3"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Schumann U, Liu L, Aggio-Bruce R, Cioanca AV, Shariev A, Madigan MC, et al. Spatial transcriptomics reveals regionally altered gene expression that drives retinal degeneration. Communications Biology. 2025; 8: 629.  [Erratum in: Commun Biol. 2025 Jul 7;8(1):1013. doi: 10.1038\/s42003-025-08451-8. PMID: 40251274; PMCID: PMC12008306.]","DOI":"10.1038\/s42003-025-07887-2"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Lv K, Ying H, Hu G, Hu J, Jian Q, Zhang F. Integrated multi-omics reveals the activated retinal microglia with intracellular metabolic reprogramming contributes to inflammation in STZ-induced early diabetic retinopathy. Frontiers in Immunology. 2022; 13: 942768.","DOI":"10.3389\/fimmu.2022.942768"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Jiang F, Lei C, Chen Y, Zhou N, Zhang M. The complement system and diabetic retinopathy. Survey of Ophthalmology. 2024; 69: 575\u2013584.","DOI":"10.1016\/j.survophthal.2024.02.004"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Smith JM, Mandava N, Tirado-Gonzalez V, Garcia-Santisteban R, Geiger MD, Patnaik JL, et al. Correlation of Complement Activation in Aqueous and Vitreous in Patients With Proliferative Diabetic Retinopathy. Translational Vision Science & Technology. 2022; 11: 13.","DOI":"10.1167\/tvst.11.4.13"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"Mandava N, Tirado-Gonzalez V, Geiger MD, Patnaik JL, Frazer-Abel A, Lynch AM, et al. Complement Activation in the Vitreous of Patients With Proliferative Diabetic Retinopathy. Investigative Ophthalmology & Visual Science. 2020; 61: 39.","DOI":"10.1167\/iovs.61.11.39"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. New insights into the immune functions of complement. Nature Reviews. Immunology. 2019; 19: 503\u2013516.","DOI":"10.1038\/s41577-019-0168-x"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Lei Y, Wang Y, Tang S, Yang J, Lai D, Qiu Q. The adaptive immune system in the retina of diabetics. Survey of Ophthalmology. 2025; 70: 241\u2013254.","DOI":"10.1016\/j.survophthal.2024.11.005"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Herdade AS, Silva IM, Calado \u00c2, Saldanha C, Nguyen NH, Hou I, et al. Effects of Diabetes on Microcirculation and Leukostasis in Retinal and Non-Ocular Tissues: Implications for Diabetic Retinopathy. Biomolecules. 2020; 10: 1583.","DOI":"10.3390\/biom10111583"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"van der Wijk AE, Hughes JM, Klaassen I, Van Noorden CJF, Schlingemann RO. Is leukostasis a crucial step or epiphenomenon in the pathogenesis of diabetic retinopathy? Journal of Leukocyte Biology. 2017; 102: 993\u20131001.","DOI":"10.1189\/jlb.3RU0417-139"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"Gettinger K, Lee D, Tomita Y, Negishi K, Kurihara T. Diabetic Retinopathy, a Comprehensive Overview on Pathophysiology and Relevant Experimental Models. International Journal of Molecular Sciences. 2025; 26: 9882.","DOI":"10.3390\/ijms26209882"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"Joussen AM, Poulaki V, Qin W, Kirchhof B, Mitsiades N, Wiegand SJ, et al. Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. The American Journal of Pathology. 2002; 160: 501\u2013509.","DOI":"10.1016\/S0002-9440(10)64869-9"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Xie X, Li F, Wu Q, Zeng C, Chen X, Wang W, et al. Imbalance of T cell subsets: a core event that mediates the progression of T2DM and its complications. Frontiers in Immunology. 2025; 16: 1688392.","DOI":"10.3389\/fimmu.2025.1688392"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Xia C, Rao X, Zhong J. Role of T Lymphocytes in Type 2 Diabetes and Diabetes-Associated Inflammation. Journal of Diabetes Research. 2017; 2017: 6494795.","DOI":"10.1155\/2017\/6494795"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"Takeuchi M, Sato T, Tanaka A, Muraoka T, Taguchi M, Sakurai Y, et al. Elevated Levels of Cytokines Associated with Th2 and Th17 Cells in Vitreous Fluid of Proliferative Diabetic Retinopathy Patients. PloS One. 2015; 10: e0137358.","DOI":"10.1371\/journal.pone.0137358"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"Soto-Heredero G, G\u00f3mez de Las Heras MM, Gaband\u00e9-Rodr\u00edguez E, Oller J, Mittelbrunn M. Glycolysis - a key player in the inflammatory response. The FEBS Journal. 2020; 287: 3350\u20133369.","DOI":"10.1111\/febs.15327"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"Yang DR, Wang MY, Zhang CL, Wang Y. Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications. Frontiers in Endocrinology. 2024; 15: 1359255.","DOI":"10.3389\/fendo.2024.1359255"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"Chakravarthy H, Beli E, Navitskaya S, O\u2019Reilly S, Wang Q, Kady N, et al. Imbalances in Mobilization and Activation of Pro-Inflammatory and Vascular Reparative Bone Marrow-Derived Cells in Diabetic Retinopathy. PloS One. 2016; 11: e0146829.","DOI":"10.1371\/journal.pone.0146829"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"Liu B, Hu Y, Wu Q, Zeng Y, Xiao Y, Zeng X, et al. Qualitative and Quantitative Analysis of B-Cell-Produced Antibodies in Vitreous Humor of Type 2 Diabetic Patients with Diabetic Retinopathy. Journal of Diabetes Research. 2020; 2020: 4631290.","DOI":"10.1155\/2020\/4631290"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Zhao B, Zhao Y, Sun X. Mechanism and therapeutic targets of circulating immune cells in diabetic retinopathy. Pharmacological Research. 2024; 210: 107505.","DOI":"10.1016\/j.phrs.2024.107505"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"Twarda-Clapa A, Olczak A, Bia\u0142kowska AM, Kozio\u0142kiewicz M. Advanced Glycation End-Products (AGEs): Formation, Chemistry, Classification, Receptors, and Diseases Related to AGEs. Cells. 2022; 11: 1312.","DOI":"10.3390\/cells11081312"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"Lu Z, Fan B, Li Y, Zhang Y. RAGE plays key role in diabetic retinopathy: a review. Biomedical Engineering Online. 2023; 22: 128.","DOI":"10.1186\/s12938-023-01194-9"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"Katagiri M, Shoji J, Inada N, Kato S, Kitano S, Uchigata Y. Evaluation of vitreous levels of advanced glycation end products and angiogenic factors as biomarkers for severity of diabetic retinopathy. 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Frontiers in Bioscience (Landmark Edition). 2023; 28: 153.","DOI":"10.31083\/j.fbl2807153"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"Guo Y, Gu R, Gan D, Hu F, Li G, Xu G. Mitochondrial DNA drives noncanonical inflammation activation via cGAS-STING signaling pathway in retinal microvascular endothelial cells. Cell Communication and Signaling: CCS. 2020; 18: 172.","DOI":"10.1186\/s12964-020-00637-3"},{"key":"ref74","doi-asserted-by":"publisher","unstructured":"Hu B, Ma JX, Duerfeldt AS. The cGAS-STING pathway in diabetic retinopathy and age-related macular degeneration. Future Medicinal Chemistry. 2023; 15: 717\u2013729.","DOI":"10.4155\/fmc-2022-0301"},{"key":"ref75","doi-asserted-by":"publisher","unstructured":"Kowluru RA, Mohammad G, Kumar J. Impaired Removal of the Damaged Mitochondria in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy. Molecular Neurobiology. 2024; 61: 188\u2013199.","DOI":"10.1007\/s12035-023-03534-1"},{"key":"ref76","doi-asserted-by":"publisher","unstructured":"Nian S, Lo ACY, Mi Y, Ren K, Yang D. Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets. Eye and Vision (London, England). 2021; 8: 15.","DOI":"10.1186\/s40662-021-00239-1"},{"key":"ref77","doi-asserted-by":"publisher","unstructured":"Sim\u00f3 R, Sim\u00f3-Servat O, Bogdanov P, Hern\u00e1ndez C. Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy. Pharmaceutics. 2021; 13: 1320.","DOI":"10.3390\/pharmaceutics13081320"},{"key":"ref78","doi-asserted-by":"publisher","unstructured":"Eggers ED, Carreon TA. The effects of early diabetes on inner retinal neurons. Visual Neuroscience. 2020; 37: E006.","DOI":"10.1017\/S095252382000005X"},{"key":"ref79","doi-asserted-by":"publisher","unstructured":"Lynch SK, Abr\u00e0moff MD. Diabetic retinopathy is a neurodegenerative disorder. Vision Research. 2017; 139: 101\u2013107.","DOI":"10.1016\/j.visres.2017.03.003"},{"key":"ref80","doi-asserted-by":"publisher","unstructured":"Wang NL. Neurodegeneration in Diabetic Retinopathy: Current Concepts and Therapeutic Implications. Chinese Medical Journal. 2016; 129: 3001\u20133003.","DOI":"10.4103\/0366-6999.195478"},{"key":"ref81","doi-asserted-by":"publisher","unstructured":"Ratra D, Nagarajan R, Dalan D, Prakash N, Kuppan K, Thanikachalam S, et al. Early structural and functional neurovascular changes in the retina in the prediabetic stage. Eye (London, England). 2021; 35: 858\u2013867.","DOI":"10.1038\/s41433-020-0984-z"},{"key":"ref82","doi-asserted-by":"publisher","unstructured":"Moran EP, Wang Z, Chen J, Sapieha P, Smith LEH, Ma JX. Neurovascular cross talk in diabetic retinopathy: Pathophysiological roles and therapeutic implications. American Journal of Physiology. 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Frontiers in Physiology. 2018; 9: 820.","DOI":"10.3389\/fphys.2018.00820"},{"key":"ref86","doi-asserted-by":"publisher","unstructured":"Nippert AR, Newman EA. Regulation of blood flow in diabetic retinopathy. Visual Neuroscience. 2020; 37: E004.","DOI":"10.1017\/S0952523820000036"},{"key":"ref87","doi-asserted-by":"publisher","unstructured":"Liu K, Zhu T, Gao M, Yin X, Zheng R, Yan Y, et al. Functional OCT angiography reveals early retinal neurovascular dysfunction in diabetes with capillary resolution. Biomedical Optics Express. 2023; 14: 1670\u20131684.","DOI":"10.1364\/BOE.485940"},{"key":"ref88","doi-asserted-by":"publisher","unstructured":"Yuan PHS, Athwal A, Shalaby M, Mehnert A, Yu DY, Preti RC, et al. Retinal capillary perfusion heterogeneity in diabetic retinopathy detected by optical coherence tomography angiography. International Journal of Retina and Vitreous. 2024; 10: 12.","DOI":"10.1186\/s40942-024-00528-6"},{"key":"ref89","doi-asserted-by":"publisher","unstructured":"Becker K, Klein H, Simon E, Viollet C, Haslinger C, Leparc G, et al. In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy. Scientific Reports. 2021; 11: 10494.","DOI":"10.1038\/s41598-021-88698-3"},{"key":"ref90","doi-asserted-by":"publisher","unstructured":"Zhang X, Liu Y, Xia M, Yang M, Wu Y, Zhang F. Multi-omics analysis of potential metabolic networks linking peripheral metabolic changes to inflammatory retinal conditions in STZ-induced early diabetic retinopathy. Biochemistry and Biophysics Reports. 2025; 43: 102182.","DOI":"10.1016\/j.bbrep.2025.102182"},{"key":"ref91","doi-asserted-by":"publisher","unstructured":"Zuo J, Lan Y, Hu H, Hou X, Li J, Wang T, et al. 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Frontiers in Endocrinology. 2023; 14: 1229089.","DOI":"10.3389\/fendo.2023.1229089"},{"key":"ref95","doi-asserted-by":"publisher","unstructured":"Zhou H, Xu Q, Li H, Hu Y, Kuang H. Proteomics identifies new potential therapeutic targets of diabetic retinopathy. Bioengineered. 2022; 13: 9916\u20139927.","DOI":"10.1080\/21655979.2022.2062185"},{"key":"ref96","doi-asserted-by":"publisher","unstructured":"Zhang J, Wang Y, Wu X, Zhang S, Cai D, Feng Y, et al. Vitreous Olink Proteomics Uncovers Novel Inflammatory Proteins in Patients with Proliferative Diabetic Retinopathy. Journal of Proteome Research. 2025; 24: 4653\u20134664.","DOI":"10.1021\/acs.jproteome.5c00394"},{"key":"ref97","doi-asserted-by":"publisher","unstructured":"Sundstrom JM, Hern\u00e1ndez C, Weber SR, Zhao Y, Dunklebarger M, Tiberti N, et al. Proteomic Analysis of Early Diabetic Retinopathy Reveals Mediators of Neurodegenerative Brain Diseases. 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Diabetologia. 2021; 64: 70\u201382.","DOI":"10.1007\/s00125-020-05309-y"},{"key":"ref101","doi-asserted-by":"publisher","unstructured":"Luo X, Xue D. Potential mechanisms of epigenetic regulation in diabetic retinopathy from the perspectives of multi-omics. Diabetology & Metabolic Syndrome. 2025; 17: 155.","DOI":"10.1186\/s13098-025-01723-7"},{"key":"ref102","doi-asserted-by":"publisher","unstructured":"Li B, Yim MM, Jin YX, Tao BK, Xie JS, Balas M, et al. Circulating Cell-Free DNA as an Epigenetic Biomarker for Early Diabetic Retinopathy: A Narrative Review. 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