O-linked β-N-acetylglucosamine modification in diabetic foot ulcer pathogenesis

Abstract

O-linked β-D-N-acetylglucosamine (O-GlcNAc) modification represents a common form of posttranslational glycosylation orchestrated by two pivotal enzymes, namely, O-GlcNAc transferase and O-GlcNAcase. In recent years, emerging research has revealed a significant association between O-GlcNAc modification and the pathogenesis of diabetic foot ulcers (DFUs). Elevated O-GlcNAc levels under high-glucose conditions contribute to the pathogenesis of DFUs by modifying specific proteins, which are implicated in peripheral neuropathy, peripheral vascular disease, and impaired chronic wound healing. This process includes prolonged inflammation, compromised granulation tissue formation, disordered re-epithelialization, and blocked tissue remodelling. This review focuses on the pathogenesis of DFUs and on the correlation between protein O-GlcNAc modification and DFUs, offering potential new insights for the diagnosis and treatment of this condition.

Keywords

O-linked β-D-N-acetylglucosamine modification / Diabetic foot ulcers / Pathogenesis / peripheral neuropathy / Peripheral arterial disease / Wound healing / Metabolic dysregulation / therapeutic target

References

[1] Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas, 9th edition. Diabetes Res Clin Pract. 2019; 157: 107843. https://doi.org/10.1016/j.diabres.2019.107843.

[2] Edmonds M, Manu C, Vas P. The current burden of diabetic foot disease. J Clin Orthop Trauma. 2021; 17: 88-93. https://doi.org/10.1016/j.jcot.2021.01.017.

[3] Armstrong DG, Tan TW, Boulton AJM, Bus SA. Diabetic foot ulcers: a review. Jama. 2023; 330: 62-75. https://doi.org/10.1001/jama.2023.10578.

[4] Lipsky BA, Senneville É, Abbas ZG, Aragón-Sánchez J, Diggle M, Embil JM, et al. Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020; 36: e3280. https://doi.org/10.1002/dmrr.3280.

[5] Jeffcoate W, Boyko EJ, Game F, Cowled P, Senneville E, Fitridge R. Causes, prevention, and management of diabetes-related foot ulcers. Lancet Diabetes Endocrinol. 2024; 12: 472-82. https://doi.org/10.1016/S2213-8587(24)00110-4.

[6] Li Y, Leng Y, Liu Y, Zhong J, Li J, Zhang S, et al. Advanced multifunctional hydrogels for diabetic foot ulcer healing: active substances and biological functions. J Diabetes. 2024; 16: e13537. https://doi.org/10.1111/1753-0407.13537.

[7] Mohsin F, Javaid S, Tariq M, Mustafa M. Molecular immunological mechanisms of impaired wound healing in diabetic foot ulcers (DFU), current therapeutic strategies and future directions. Int Immunopharmacol. 2024; 139: 112713. https://doi.org/10.1016/j.intimp.2024.112713.

[8] Liu X, Huang GT, Wu J. Research advances on the application of free flaps in limb salvage treatment of patients with diabetic foot ulcers. Chin J Burns Wounds. 2024; 40: 985-90.

[9] Liu J, Yuan X, Liu J, Yuan G, Sun Y, Zhang D, et al. Risk factors for diabetic peripheral neuropathy, peripheral artery disease, and foot deformity among the population with diabetes in Beijing, China: a Multicenter, cross-sectional study. Front Endocrinol (Lausanne). 2022; 13: 824215. https://doi.org/10.3389/fendo.2022.824215.

[10] Baron JM, Glatz M, Proksch E. Optimal support of wound healing: new insights. Dermatology. 2020; 236: 593-600. https://doi.org/10.1159/000505291.

[11] Huang F, Lu X, Yang Y, Yang Y, Li Y, Kuai L, et al. Microenvironment-based diabetic foot ulcer nanomedicine. Adv Sci (Weinh). 2023; 10: e2203308. https://doi.org/10.1002/advs.202203308.

[12] Xu J, Han X, He L, Feng S, Sun D, Cao C, et al. Analysis of biofilm genes and quorum sensing genes of carbapenem resistant Acinetobacter baumannii in the wounds of diabetic foot patients. Chin J Burns Wounds. 2024; 40: 1166-75.

[13] Deng H, Li B, Shen Q, Zhang C, Kuang L, Chen R, et al. Mechanisms of diabetic foot ulceration: a review. J Diabetes. 2023; 15: 299-312. https://doi.org/10.1111/1753-0407.13372.

[14] Kurian SJ, Baral T, Benson R, Munisamy M, Saravu K, Rodrigues GS, et al. Association of vitamin D status and vitamin D receptor polymorphism in diabetic foot ulcer patients: a prospective observational study in a south-Indian tertiary healthcare facility. Int Wound J. 2024; 21: e70027. https://doi.org/10.1111/iwj.70027.

[15] Suresh AP, Vijayarengan M, Aggarwal P, Soundaram R, Gnanesh Kumar BS, Sundaram GM. A site-specific phosphorylation in FSTL1 determines its promigratory role in wound healing. Biochimie. 2024; 225: 106-13. https://doi.org/10.1016/j.biochi.2024.05.016.

[16] Torres CR, Hart GW. Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J Biol Chem. 1984; 259: 3308-17. https://doi.org/10.1016/S0021-9258(17)43295-9.

[17] Lee BE, Suh P-G, Kim J-I. O-GlcNAcylation in health and neurodegenerative diseases. Exp Mol Med. 2021; 53: 1674-82. https://doi.org/10.1038/s12276-021-00709-5.

[18] Huang R, Tian S, Zhang H, Zhu W, Wang S. Chronic hyperglycemia induces tau hyperphosphorylation by downregulating OGT-involved O-GlcNAcylation in vivo and in vitro. Brain Res Bull. 2020; 156: 76-85. https://doi.org/10.1016/j.brainresbull.2020.01.006.

[19] Dong W, Imdad L, Xu S, Wang Y, Liu C, Song S, et al. O-GlcNAc modification is a promising therapeutic target for diabetic retinopathy. Int J Mol Sci. 2024; 25: 6286. https://doi.org/10.3390/ijms25116286.

[20] Qi B, Chen Y, Chai S, Lu X, Kang L. O-linked β-N-acetylglucosamine (O-GlcNAc) modification: emerging pathogenesis and a therapeutic target of diabetic nephropathy. Diabetic Medicine: A Journal of the British Diabetic Association. 2025; 42: e15436. https://doi.org/10.1111/dme.15436.

[21] Figueroa-Romero C, Sadidi M, Feldman EL. Mechanisms of disease: the oxidative stress theory of diabetic neuropathy. Rev Endocr Metab Disord. 2008; 9: 301-14. https://doi.org/10.1007/s11154-008-9104-2.

[22] Wu HF, Huang CW, Art J, Liu HX, Hart GW, Zeltner N. O-GlcNAcylation is crucial for sympathetic neuron development, maintenance, functionality and contributes to peripheral neuropathy. Front Neurosci. 2023; 17: 1137847. https://doi.org/10.3389/fnins.2023.1137847.

[23] Tao K, Cao T, Hao T. Mechanisms and intervention strategies of angiogenesis disorders in diabetic foot ulcers. Chin J Burns Wounds. 2025; 41: 120-6.

[24] Khanal S, Bhavnani N, Mathias A, Lallo J, Gupta S, Ohanyan V, et al. Deletion of smooth muscle O-GlcNAc transferase prevents development of atherosclerosis in western diet-fed Hyperglycemic ApoE(−/−) mice In vivo. Int J Mol Sci. 2023; 24: 7899. https://doi.org/10.3390/ijms24097899.

[25] Very N, Vercoutter-Edouart AS, Lefebvre T, Hardiville S, El Yazidi-Belkoura I. Cross-dysregulation of O-GlcNAcylation and PI3K/AKT/mTOR Axis in human chronic diseases. Front Endocrinol (Lausanne). 2018; 9: 602. https://doi.org/10.3389/fendo.2018.00602.

[26] Zhang J, Yang P, Liu D, Gao M, Wang J, Yu T, et al. Inhibiting hyper-O-GlcNAcylation of c-Myc accelerate diabetic wound healing by alleviating keratinocyte dysfunction. Burns & Trauma. 2021; 9: tkab031. https://doi.org/10.1093/burnst/tkab031.

[27] Qiu Y, Yu W, Zhang X, Zhang M, Ni Y, Lai S, et al. Upregulation of OGT-mediated EZH2 O-GlcNAcylation promotes human umbilical vein endothelial cell proliferation, invasion, migration, and tube formation in gestational diabetes mellitus. Cell Biochem Biophys. 2025; 83: 2461-70. https://doi.org/10.1007/s12013-024-01655-5.

[28] Very N, Staels B, Eeckhoute J. Increased O-GlcNAcylation connects metabolic to transcriptional reprogramming during pathophysiological cell activation. Trends Cell Biol. 2024; 34: 988-91. https://doi.org/10.1016/j.tcb.2024.10.007.

[29] Marshall S, Bacote V, Traxinger RR. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem. 1991; 266: 4706-12. https://doi.org/10.1016/S0021-9258(19)67706-9.

[30] Chiaradonna F, Ricciardiello F, Palorini R. The nutrient-sensing Hexosamine biosynthetic pathway as the hub of cancer metabolic rewiring. Cells. 2018; 7: 53. https://doi.org/10.3390/cells7060053.

[31] Yang X, Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol. 2017; 18: 452-65. https://doi.org/10.1038/nrm.2017.22.

[32] Jínek M, Rehwinkel J, Lazarus BD, Izaurralde E, Hanover JA, Conti E. The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha. Nat Struct Mol Biol. 2004; 11: 1001-7. https://doi.org/10.1038/nsmb833.

[33] Pathak S, Alonso J, Schimpl M, Rafie K, Blair DE, Borodkin VS, et al. The active site of O-GlcNAc transferase imposes constraints on substrate sequence. Nat Struct Mol Biol. 2015; 22: 744-50. https://doi.org/10.1038/nsmb.3063.

[34] Hanover JA, Yu S, Lubas WB, Shin SH, Ragano-Caracciola M, Kochran J, et al. Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene. Arch Biochem Biophys. 2003; 409: 287-97. https://doi.org/10.1016/S0003-9861(02)00578-7.

[35] Stephen HM, Adams TM, Wells L. Regulating the regulators: mechanisms of substrate selection of the O-GlcNAc cycling enzymes OGT and OGA. Glycobiology. 2021; 31: 724-33. https://doi.org/10.1093/glycob/cwab005.

[36] Li B, Li H, Lu L, Jiang J. Structures of human O-GlcNAcase and its complexes reveal a new substrate recognition mode. Nat Struct Mol Biol. 2017; 24: 362-9. https://doi.org/10.1038/nsmb.3390.

[37] Schimpl M, Schüttelkopf AW, Borodkin VS, van Aalten DM. Human OGA binds substrates in a conserved peptide recognition groove. Biochem J. 2010; 432: 1-12. https://doi.org/10.1042/BJ20101338.

[38] Pagesy P, Bouaboud A, Feng Z, Hulin P, Issad T. Short O-GlcNAcase is targeted to the mitochondria and regulates mitochondrial reactive oxygen species level. Cells. 2022; 11: 1827. https://doi.org/10.3390/cells11111827.

[39] Gao Y, Wells L, Comer FI, Parker GJ, Hart GW. Dynamic O-glycosylation of nuclear and cytosolic proteins: cloning and characterization of a neutral, cytosolic beta-N-acetylglucosaminidase from human brain. J Biol Chem. 2001; 276: 9838-45. https://doi.org/10.1074/jbc.M010420200.

[40] Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002; 298: 1912-34. https://doi.org/10.1126/science.1075762.

[41] Hwang H, Rhim H. Functional significance of O-GlcNAc modification in regulating neuronal properties. Pharmacol Res. 2018; 129: 295-307. https://doi.org/10.1016/j.phrs.2017.12.006.

[42] Wulff-Fuentes E, Berendt RR, Massman L, Danner L, Malard F, Vora J, et al. The human O-GlcNAcome database and meta-analysis. Scientific Data. 2021; 8: 25. https://doi.org/10.1038/s41597-021-00810-4.

[43] Wells L, Hart GW. O-GlcNAcylation: a major nutrient/stress sensor that regulates cellular physiology. J Biol Chem. 2024; 300: 107635. https://doi.org/10.1016/j.jbc.2024.107635.

[44] Dasari S, Kalyaanamoorthy S. Impact of phosphorylation and O-GlcNAcylation on the binding affinity of R4 tau peptide to microtubule and its conformational preference upon dissociation. J Chem Inf Model. 2025; 65: 1570-84. https://doi.org/10.1021/acs.jcim.4c02109.

[45] Jiang X, Yang Y, Li X, Li T, Yu T, Fu X. Lactylation: an innovative approach to disease control. Aging Dis. 2024; 16: 2130-50. https://doi.org/10.14336/AD.2024.0918.

[46] Lu K, Han D. A review of the mechanism of succinylation in cancer. Medicine. 2022; 101:e31493. https://doi.org/10.1097/MD.0000000000031493.

[47] Yavuz DG.Chapter 1-Classification, risk factors, and clinical presentation diabetic neuropathy. In: Tavakoli M (ed).Diabetic Neuropathy. Elsevier, Amsterdam, The Netherlands, 2022, 1-9. 10.1016/B978-0-12-820669-0.00014-1.

[48] Albers JW, Pop-Busui R. Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. Curr Neurol Neurosci Rep. 2014; 14: 473. https://doi.org/10.1007/s11910-014-0473-5.

[49] Calcutt NA.Diabetic neuropathy and neuropathic pain: a (con)fusion of pathogenic mechanisms? Pain. 2020; 161: S65-86. https://doi.org/10.1097/j.pain.0000000000001922.

[50] Brownlee M.Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414: 813-20. https://doi.org/10.1038/414813a.

[51] Datta PK, Blake MC, Moses HL. Regulation of plasminogen activator inhibitor-1 expression by transforming growth factor-beta-induced physical and functional interactions between smads and Sp1. J Biol Chem. 2000; 275: 40014-9. https://doi.org/10.1074/jbc.C000508200.

[52] Hafer-Macko CE, Ivey FM, Sorkin JD, Macko RF. Microvascular tissue plasminogen activator is reduced in diabetic neuropathy. Neurology. 2007; 69: 268-74. https://doi.org/10.1212/01.wnl.0000266391.20707.83.

[53] Yao K, Tan J, Gu WZ, Ye PP, Wang KJ. Reactive oxygen species mediates the apoptosis induced by transforming growth factor beta(2) in human lens epithelial cells. Biochem Biophys Res Commun. 2007; 354: 278-83. https://doi.org/10.1016/j.bbrc.2006.12.198.

[54] Schmidt RE, Parvin CA, Green KG. Synaptic ultrastructural alterations anticipate the development of Neuroaxonal dystrophy in sympathetic ganglia of aged and diabetic mice. J Neuropathol Exp Neurol. 2008; 67: 1166-86. https://doi.org/10.1097/NEN.0b013e318190d6db.

[55] Hao T, Cao T, Ji P, Zhang WF, Tao K. Research advances on the role of Schwann cells in diabetic peripheral neuropathy. Zhonghua Shao Shang Yu Chuang Mian Xiu Fu Za Zhi. 2023; 39: 1190-4. https://doi.org/10.3760/cma.j.cn501225-20230727-00019.

[56] Kim S, Maynard JC, Strickland A, Burlingame AL, Milbrandt J. Schwann cell O-GlcNAcylation promotes peripheral nerve remyelination via attenuation of the AP-1 transcription factor JUN. Proc Natl Acad Sci USA. 2018; 115: 8019-24. https://doi.org/10.1073/pnas.1805538115.

[57] Park JH, Nakamura Y, Li W, Hamanaka G, Arai K, Lo EH, et al. Effects of O-GlcNAcylation on functional mitochondrial transfer from astrocytes. J Cereb Blood Flow Metab. 2021; 41: 1523-35. https://doi.org/10.1177/0271678X20969588.

[58] Park JH, Tanaka M, Nakano T, Licastro E, Nakamura Y, Li W, et al. O-GlcNAcylation is essential for therapeutic mitochondrial transplantation. Communications Medicine. 2023; 3: 169. https://doi.org/10.1038/s43856-023-00402-w.

[59] Taub DG, Awal MR, Gabel CV. O-GlcNAc Signaling orchestrates the regenerative response to neuronal injury in Caenorhabditis elegans. Cell Rep. 2018; 24: 1931-1938.e3. https://doi.org/10.1016/j.celrep.2018.07.078.

[60] Su C, Schwarz TL. O-GlcNAc transferase is essential for sensory neuron survival and maintenance. J Neurosci. 2017; 37: 2125-36. https://doi.org/10.1523/JNEUROSCI.3384-16.2017.

[61] Ansari SA, Emerald BS. The role of insulin resistance and protein O-GlcNAcylation in neurodegeneration. Front Neurosci. 2019; 13: 473. https://doi.org/10.3389/fnins.2019.00473.

[62] Chuter V, Quigley F, Tosenovsky P, Ritter JC, Charles J, Cheney J, et al. Australian guideline on diagnosis and management of peripheral artery disease: part of the 2021 Australian evidence-based guidelines for diabetes-related foot disease. Journal of Foot and Ankle Research. 2022; 15: 51. https://doi.org/10.1186/s13047-022-00550-7.

[63] Barnes JA, Eid MA, Creager MA, Goodney PP. Epidemiology and risk of amputation in patients with diabetes mellitus and peripheral artery disease. Arterioscler Thromb Vasc Biol. 2020; 40: 1808-17. https://doi.org/10.1161/ATVBAHA.120.314595.

[64] Boyko EJ, Monteiro-Soares M, Wheeler SGB. Peripheral Arterial Disease, Foot Ulcers, Lower Extremity Amputations, and Diabetes. In: Cowie CC, Casagrande SS, Menke A, Cissell MA, Eberhardt MS, Meigs JB, et al. (eds).Diabetes in America. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases (US), 2018.

[65] Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab. 2009; 94: 3171-82. https://doi.org/10.1210/jc.2008-2534.

[66] Byon CH, Kim SW. Regulatory effects of O-GlcNAcylation in vascular smooth muscle cells on diabetic vasculopathy. J Lipid Atheroscler. 2020; 9: 243-54. https://doi.org/10.12997/jla.2020.9.2.243.

[67] Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA. 2000; 97: 12222-6. https://doi.org/10.1073/pnas.97.22.12222.

[68] Shrikhande GV, Scali ST, da Silva CG, Damrauer SM, Csizmadia E, Putheti P, et al. O-glycosylation regulates ubiquitination and degradation of the anti-inflammatory protein A20 to accelerate atherosclerosis in diabetic ApoE-null mice. PLoS One. 2010; 5: e14240. https://doi.org/10.1371/journal.pone.0014240.

[69] Heath JM, Sun Y, Yuan K, Bradley WE, Litovsky S, Dell’Italia LJ, et al. Activation of AKT by O-linked N-acetylglucosamine induces vascular calcification in diabetes mellitus. Circ Res. 2014; 114: 1094-102. https://doi.org/10.1161/CIRCRESAHA.114.302968.

[70] Makino A, Dai A, Han Y, Youssef KD, Wang W, Donthamsetty R, et al. O-GlcNAcase overexpression reverses coronary endothelial cell dysfunction in type 1 diabetic mice. Am J Physiol Cell Physiol. 2015; 309: C593-9. https://doi.org/10.1152/ajpcell.00069.2015.

[71] Macdonald KE, Boeckh S, Stacey HJ, Jones JD. The microbiology of diabetic foot infections: a meta-analysis. BMC Infect Dis. 2021; 21: 770. https://doi.org/10.1186/s12879-021-06516-7.

[72] Goldberg SR, Diegelmann RF. What makes wounds chronic. Surg Clin North Am. 2020; 100: 681-93. https://doi.org/10.1016/j.suc.2020.05.001.

[73] Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. Type 2 diabetes and its impact on the immune system. Curr Diabetes Rev. 2020; 16: 442-9. https://doi.org/10.2174/1573399815666191024085838.

[74] Hu J, Gao Q, Yang Y, Xia J, Zhang W, Chen Y, et al. Hexosamine biosynthetic pathway promotes the antiviral activity of SAMHD1 by enhancing O-GlcNAc transferase-mediated protein O-GlcNAcylation. Theranostics. 2021; 11: 805-23. https://doi.org/10.7150/thno.50230.

[75] Kim M, Morales LD, Jang IS, Cho YY, Kim DJ. Protein tyrosine phosphatases as potential regulators of STAT3 Signaling. Int J Mol Sci. 2018; 19: 2708. https://doi.org/10.3390/ijms19092708.

[76] Li X, Zhang Z, Li L, Gong W, Lazenby AJ, Swanson BJ, et al. Myeloid-derived cullin 3 promotes STAT3 phosphorylation by inhibiting OGT expression and protects against intestinal inflammation. J Exp Med. 2017; 214: 1093-109. https://doi.org/10.1084/jem.20161105.

[77] Freemerman AJ, Johnson AR, Sacks GN, Milner JJ, Kirk EL, Troester MA, et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem. 2014; 289: 7884-96. https://doi.org/10.1074/jbc.M113.522037.

[78] Lin S, Wang Q, Huang X, Feng J, Wang Y, Shao T, et al. Wounds under diabetic milieu: the role of immune cellar components and signaling pathways. Biomed Pharmacother. 2023; 157: 114052. https://doi.org/10.1016/j.biopha.2022.114052.

[79] Rehak L, Giurato L, Meloni M, Panunzi A, Manti GM, Uccioli L. The immune-centric revolution in the diabetic foot: monocytes and lymphocytes role in wound healing and tissue regeneration-a narrative review. J Clin Med. 2022; 11: 889. https://doi.org/10.3390/jcm11030889.

[80] Puchalowicz K, Rac ME. The multifunctionality of CD36 in diabetes mellitus and its complications-update in pathogenesis, Treatment and Monitoring. Cells. 2020; 9: 1877. https://doi.org/10.3390/cells9081877.

[81] Louiselle AE, Niemiec SM, Zgheib C, Liechty KW. Macrophage polarization and diabetic wound healing. Transl Res. 2021; 236: 109-16. https://doi.org/10.1016/j.trsl.2021.05.006.

[82] Mowat AG, Baum J. Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus. N Engl J Med. 1971; 284: 621-7. https://doi.org/10.1056/NEJM197103252841201.

[83] Dowey R, Iqbal A, Heller SR, Sabroe I, Prince LR. A bittersweet response to infection in diabetes; targeting neutrophils to modify inflammation and improve host immunity. Front Immunol. 2021; 12: 678771. https://doi.org/10.3389/fimmu.2021.678771.

[84] Liu D, Yang P, Gao M, Yu T, Shi Y, Zhang M, et al. NLRP3 activation induced by neutrophil extracellular traps sustains inflammatory response in the diabetic wound. Clin Sci (Lond). 2019; 133: 565-82. https://doi.org/10.1042/CS20180600.

[85] Zanotto C, Olivon V, Mestriner F, Alves Filho J, Carneiro F, Tostes R. Effects of augmented O-GlcNAcylation on activation and differentiation of macrophages. FASEB J. 2015; 29: 621.615. https://doi.org/10.1096/fasebj.29.1_supplement.621.15.

[86] Yang WH, Park SY, Nam HW, Kim DH, Kang JG, Kang ES, et al. NFkappaB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions. Proc Natl Acad Sci USA. 2008; 105: 17345-50. https://doi.org/10.1073/pnas.0806198105.

[87] Mussbacher M, Derler M, Basílio J, Schmid JA. NF-κB in monocytes and macrophages-an inflammatory master regulator in multitalented immune cells. Front Immunol. 2023; 14: 1134661. https://doi.org/10.3389/fimmu.2023.1134661.

[88] Ramakrishnan P, Clark PM, Mason DE, Peters EC, Hsieh-Wilson LC, Baltimore D. Activation of the transcriptional function of the NF-κB protein c-Rel by O-GlcNAc glycosylation. Sci Signal. 2013; 6: ra75. https://doi.org/10.1126/scisignal.2004097.

[89] Machacek M, Saunders H, Zhang Z, Tan EP, Li J, Li T, et al. Elevated O-GlcNAcylation enhances pro-inflammatory Th17 function by altering the intracellular lipid microenvironment. J Biol Chem. 2019; 294: 8973-90. https://doi.org/10.1074/jbc.RA119.008373.

[90] Li Y, Xie M, Men L, Du J. O-GlcNAcylation in immunity and inflammation: an intricate system (review). Int J Mol Med. 2019; 44: 363-74. https://doi.org/10.3892/ijmm.2019.4238.

[91] Tefft JB, Chen CS, Eyckmans J. Reconstituting the dynamics of endothelial cells and fibroblasts in wound closure. APL Bioeng. 2021; 5: 016102. https://doi.org/10.1063/5.0028651.

[92] Reinke JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012; 49: 35-43. https://doi.org/10.1159/000339613.

[93] La Sala L, Prattichizzo F, Ceriello A. The link between diabetes and atherosclerosis. Eur J Prev Cardiol. 2019; 26: 15-24. https://doi.org/10.1177/2047487319878373.

[94] Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res. 2010; 89: 219-29. https://doi.org/10.1177/0022034509359125.

[95] Liu H, Wang X, Gao H, Yang C, Xie C. Physiological and pathological characteristics of vascular endothelial injury in diabetes and the regulatory mechanism of autophagy. Front Endocrinol (Lausanne). 2023; 14: 1191426. https://doi.org/10.3389/fendo.2023.1191426.

[96] Masaki N, Feng B, Breton-Romero R, Inagaki E, Weisbrod RM, Fetterman JL, et al. O-GlcNAcylation mediates glucose-induced alterations in endothelial cell phenotype in human diabetes mellitus. J Am Heart Assoc. 2020; 9: e014046. https://doi.org/10.1161/JAHA.119.014046.

[97] Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest. 2001; 108: 1341-8. https://doi.org/10.1172/JCI11235.

[98] Zibrova D, Vandermoere F, Göransson O, Peggie M, Mariño KV, Knierim A, et al. GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis. Biochem J. 2017; 474: 983-1001. https://doi.org/10.1042/BCJ20160980.

[99] Lima VV, Giachini FR, Carneiro FS, Carneiro ZN, Fortes ZB, Carvalho MH, et al. Increased vascular O-GlcNAcylation augments reactivity to constrictor stimuli-VASOACTIVE PEPTIDE SYMPOSIUM. J Am Soc Hypertens. 2008; 2: 410-7. https://doi.org/10.1016/j.jash.2008.06.001.

[100] Cialdai F, Risaliti C, Monici M. Role of fibroblasts in wound healing and tissue remodeling on earth and in space. Front Bioeng Biotechnol. 2022; 10: 958381. https://doi.org/10.3389/fbioe.2022.958381.

[101] Dekoninck S, Blanpain C. Stem cell dynamics, migration and plasticity during wound healing. Nat Cell Biol. 2019; 21: 18-24. https://doi.org/10.1038/s41556-018-0237-6.

[102] Wan R, Weissman JP, Grundman K, Lang L, Grybowski DJ, Galiano RD. Diabetic wound healing: the impact of diabetes on myofibroblast activity and its potential therapeutic treatments. Wound Repair Regen. 2021; 29: 573-81. https://doi.org/10.1111/wrr.12954.

[103] Jiang H, Rhee S, Ho CH, Grinnell F. Distinguishing fibroblast promigratory and procontractile growth factor environments in 3-D collagen matrices. FASEB J. 2008; 22: 2151-60. https://doi.org/10.1096/fj.07-097014.

[104] Pedowitz NJ, Batt AR, Darabedian N, Pratt MR. MYPT1 O-GlcNAc modification regulates sphingosine-1-phosphate mediated contraction. Nat Chem Biol. 2021; 17: 169-77. https://doi.org/10.1038/s41589-020-0640-8.

[105] He J, Fan Z, Tian Y, Yang W, Zhou Y, Zhu Q, et al. Spatiotemporal activation of protein O-GlcNAcylation in living cells. J Am Chem Soc. 2022; 144: 4289-93. https://doi.org/10.1021/jacs.1c11041.

[106] Qiu Y, Shen J, Jiang W, Yang Y, Liu X, Zeng Y. Sphingosine 1-phosphate and its regulatory role in vascular endothelial cells. Histol Histopathol. 2022; 37: 213-25. https://doi.org/10.14670/HH-18-428.

[107] Chen T, Song P, He M, Rui S, Duan X, Ma Y, et al. Sphingosine-1-phosphate derived from PRP-exos promotes angiogenesis in diabetic wound healing via the S1PR1/AKT/FN1 signalling pathway. Burns & Trauma. 2023; 11: tkad003. https://doi.org/10.1093/burnst/tkad003.

[108] Smith J, Rai V. Novel factors regulating proliferation, migration, and differentiation of fibroblasts, keratinocytes, and vascular smooth muscle cells during wound healing. Biomedicines. 2024; 12: 1939. https://doi.org/10.3390/biomedicines12091939.

[109] Lan CC, Liu IH, Fang AH, Wen CH, Wu CS. Hyperglycaemic conditions decrease cultured keratinocyte mobility: implications for impaired wound healing in patients with diabetes. Br J Dermatol. 2008; 159: 1103-15. https://doi.org/10.1111/j.1365-2133.2008.08789.x.

[110] Runager K, Bektas M, Berkowitz P, Rubenstein DS. Targeting O-glycosyltransferase (OGT) to promote healing of diabetic skin wounds. J Biol Chem. 2014; 289: 5462-6. https://doi.org/10.1074/jbc.M113.513952.

[111] Sohn KC, Lee EJ, Shin JM, Lim EH, No Y, Lee JY, et al. Regulation of keratinocyte differentiation by O-GlcNAcylation. J Dermatol Sci. 2014; 75: 10-5. https://doi.org/10.1016/j.jdermsci.2014.04.010.

[112] Yang X, Su K, Roos MD, Chang Q, Paterson AJ, Kudlow JE. O-linkage of N-acetylglucosamine to Sp1 activation domain inhibits its transcriptional capability. Proc Natl Acad Sci USA. 2001; 98: 6611-6. https://doi.org/10.1073/pnas.111099998.

[113] Eckert RL, Crish JF, Efimova T, Dashti SR, Deucher A, Bone F, et al. Regulation of involucrin gene expression. J Invest Dermatol. 2004; 123: 13-22. https://doi.org/10.1111/j.0022-202X.2004.22723.x.

[114] Huang SM, Wu CS, Chiu MH, Yang HJ, Chen GS, Lan CE. High-glucose environment induced intracellular O-GlcNAc glycosylation and reduced galectin-7 expression in keratinocytes: implications on impaired diabetic wound healing. J Dermatol Sci. 2017; 87: 168-75. https://doi.org/10.1016/j.jdermsci.2017.04.014.

[115] Chang M. Restructuring of the extracellular matrix in diabetic wounds and healing: a perspective. Pharmacol Res. 2016; 107: 243-8. https://doi.org/10.1016/j.phrs.2016.03.008.

[116] Kyriakides TR, Tam JW, Bornstein P. Accelerated wound healing in mice with a disruption of the thrombospondin 2 gene. J Invest Dermatol. 1999; 113: 782-7. https://doi.org/10.1046/j.1523-1747.1999.00755.x.

[117] Kunkemoeller B, Bancroft T, Xing H, Morris AH, Luciano AK, Wu J, et al. Elevated thrombospondin 2 contributes to delayed wound healing in diabetes. Diabetes. 2019; 68: 2016-23. https://doi.org/10.2337/db18-1001.

[118] Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci. 2020; 21: 9739. https://doi.org/10.3390/ijms21249739.

[119] Lobmann R, Ambrosch A, Schultz G, Waldmann K, Schiweck S, Lehnert H. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia. 2002; 45: 1011-6. https://doi.org/10.1007/s00125-002-0868-8.

[120] Frear CC, Zang T, Griffin BR, McPhail SM, Parker TJ, Kimble RM, et al. The modulation of the burn wound environment by negative pressure wound therapy: insights from the proteome. Wound Repair Regen. 2021; 29: 288-97. https://doi.org/10.1111/wrr.12887.

[121] Long M, Rojo de la Vega M, Wen Q, Bharara M, Jiang T, Zhang R, et al. An essential role of NRF2 in diabetic wound healing. Diabetes. 2016; 65: 780-93. https://doi.org/10.2337/db15-0564.

[122] He F, Ru X, Wen T. NRF2, a transcription factor for stress response and beyond. Int J Mol Sci. 2020; 21: 4777. https://doi.org/10.3390/ijms21134777.

[123] Chen PH, Smith TJ, Wu J, Siesser PF, Bisnett BJ, Khan F, et al. Glycosylation of KEAP1 links nutrient sensing to redox stress signaling. EMBO J. 2017; 36: 2233-50. https://doi.org/10.15252/embj.201696113.

[124] Zhu Q, Zhou L, Yang Z, Lai M, Xie H, Wu L, et al. O-GlcNAcylation plays a role in tumor recurrence of hepatocellular carcinoma following liver transplantation. Med Oncol. 2012; 29: 985-93. https://doi.org/10.1007/s12032-011-9912-1.

[125] Xu S, Chisholm AD. C. Elegans epidermal wounding induces a mitochondrial ROS burst that promotes wound repair. Dev Cell. 2014; 31: 48-60. https://doi.org/10.1016/j.devcel.2014.08.002.

[126] Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 2014; 20: 1126-67. https://doi.org/10.1089/ars.2012.5149.

[127] Yuan T, Yang T, Chen H, Fu D, Hu Y, Wang J, et al. New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol. 2019; 20: 247-60. https://doi.org/10.1016/j.redox.2018.09.025.

[128] Garg SS, Gupta J. Polyol pathway and redox balance in diabetes. Pharmacol Res. 2022; 182: 106326. https://doi.org/10.1016/j.phrs.2022.106326.

[129] Tyeb S, Shiekh PA, Verma V, Kumar A. Adipose-derived stem cells (ADSCs) loaded Gelatin-Sericin-laminin Cryogels for tissue regeneration in diabetic wounds. Biomacromolecules. 2020; 21: 294-304. https://doi.org/10.1021/acs.biomac.9b01355.

[130] Lima VV, Spitler K, Choi H, Webb RC, Tostes RC. O-GlcNAcylation and oxidation of proteins: is signalling in the cardiovascular system becoming sweeter? Clin Sci (Lond). 2012; 123: 473-86. https://doi.org/10.1042/CS20110638.

[131] Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010; 107: 1058-70. https://doi.org/10.1161/CIRCRESAHA.110.223545.

[132] Rajapakse AG, Ming XF, Carvas JM, Yang Z. O-linked beta-N-acetylglucosamine during hyperglycemia exerts both anti-inflammatory and pro-oxidative properties in the endothelial system. Oxidative Med Cell Longev. 2009; 2: 172-5. https://doi.org/10.4161/oxim.2.3.8482.

[133] Li M, Yu H, Pan H, Zhou X, Ruan Q, Kong D, et al. Nrf2 suppression delays diabetic wound healing through sustained oxidative stress and inflammation. Front Pharmacol. 2019; 10: 1099. https://doi.org/10.3389/fphar.2019.01099.

[134] Cai F, Chen W, Zhao R, Liu Y. Mechanisms of Nrf2 and NF-κB pathways in diabetic wound and potential treatment strategies. Mol Biol Rep. 2023; 50: 5355-67. https://doi.org/10.1007/s11033-023-08392-7.

[135] Tan EP, McGreal SR, Graw S, Tessman R, Koppel SJ, Dhakal P, et al. Sustained O-GlcNAcylation reprograms mitochondrial function to regulate energy metabolism. J Biol Chem. 2017; 292: 14940-62. https://doi.org/10.1074/jbc.M117.797944.

[136] Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, et al. Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev. 2012; 92: 1479-514. https://doi.org/10.1152/physrev.00022.2011.

[137] Li X, Wu G, Han F, Wang K, Bai X, Jia Y, et al. SIRT1 activation promotes angiogenesis in diabetic wounds by protecting endothelial cells against oxidative stress. Arch Biochem Biophys. 2019; 661: 117-24. https://doi.org/10.1016/j.abb.2018.11.016.

[138] Han C, Gu Y, Shan H, Mi W, Sun J, Shi M, et al. O-GlcNAcylation of SIRT1 enhances its deacetylase activity and promotes cytoprotection under stress. Nat Commun. 2017; 8: 1491. https://doi.org/10.1038/s41467-017-01654-6.

[139] Yang S, Xu M, Meng G, Lu Y. SIRT3 deficiency delays diabetic skin wound healing via oxidative stress and necroptosis enhancement. J Cell Mol Med. 2020; 24: 4415-27. https://doi.org/10.1111/jcmm.15100.

[140] Park SJ, Bae JE, Jo DS, Kim JB, Park NY, Fang J, et al. Increased O-GlcNAcylation of Drp1 by amyloid-beta promotes mitochondrial fission and dysfunction in neuronal cells. Molecular Brain. 2021; 14: 6. https://doi.org/10.1186/s13041-020-00727-w.

[141] Makino A, Suarez J, Gawlowski T, Han W, Wang H, Scott BT, et al. Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes. American Journal of Physiology Regulatory, Integrative and Comparative Physiology. 2011; 300: R1296-302. https://doi.org/10.1152/ajpregu.00437.2010.

[142] O-GlcNAc transferase regulates glycolytic metabolon formation on mitochondria to enhance ATP production. Nature Metabolism. 2024; 6: 1655- 6. https://doi.org/10.1038/s42255-024-01120-w.

[143] Qiu Z, Cui J, Huang Q, Qi B, Xia Z. Roles of O-GlcNAcylation in mitochondrial homeostasis and cardiovascular diseases. Antioxidants (Basel, Switzerland). 2024; 13: 13. https://doi.org/10.3390/antiox13050571.

[144] Alghusen IM, Carman MS, Wilkins HM, Strope TA, Gimore C, Fedosyuk H, et al. O-GlcNAc impacts mitophagy via the PINK1-dependent pathway. Front Aging Neurosci. 2024; 16: 1387931. https://doi.org/10.3389/fnagi.2024.1387931.

[145] Gonzalez-Rellan MJ, Fondevila MF, Dieguez C, Nogueiras R. O-GlcNAcylation: a sweet hub in the regulation of glucose metabolism in health and disease. Front Endocrinol (Lausanne). 2022; 13: 873513. https://doi.org/10.3389/fendo.2022.873513.

[146] Liu Y, Hu YJ, Fan WX, Quan X, Xu B, Li SZ. O-GlcNAcylation: the underestimated emerging regulators of skeletal muscle physiology. Cells. 2022; 11: 1789. https://doi.org/10.3390/cells11111789.

[147] Yang Y, Fu M, Li MD, Zhang K, Zhang B, Wang S, et al. O-GlcNAc transferase inhibits visceral fat lipolysis and promotes diet-induced obesity. Nat Commun. 2020; 11: 181. https://doi.org/10.1038/s41467-019-13914-8.

[148] Li M-D, Vera NB, Yang Y, Zhang B, Ni W, Ziso-Qejvanaj E, et al. Adipocyte OGT governs diet-induced hyperphagia and obesity. Nat Commun. 2018; 9: 5103. https://doi.org/10.1038/s41467-018-07461-x.

[149] Copeland RJ, Bullen JW, Hart GW. Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity. Am J Physiol Endocrinol Metab. 2008; 295: E17-28. https://doi.org/10.1152/ajpendo.90281.2008.

[150] Lambert M, Bastide B, Cieniewski-Bernard C. Involvement of O-GlcNAcylation in the skeletal muscle physiology and physiopathology: focus on muscle metabolism. Front Endocrinol (Lausanne). 2018; 9: 578. https://doi.org/10.3389/fendo.2018.00578.

[151] Merz KE, Thurmond DC. Role of skeletal muscle in insulin resistance and glucose uptake. Compr Physiol. 2020; 10: 785-809. https://doi.org/10.1002/j.2040-4603.2020.tb00136.x.

[152] Shi H, Munk A, Nielsen TS, Daughtry MR, Larsson L, Li S, et al. Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity. Mol Metab. 2018; 11: 160-77. https://doi.org/10.1016/j.molmet.2018.02.010.

[153] Ma J, Hart GW. Protein O-GlcNAcylation in diabetes and diabetic complications. Expert Rev Proteomics. 2013; 10: 365-80. https://doi.org/10.1586/14789450.2013.820536.

[154] Cheng SS, Mody AC, Woo CM. Opportunities for therapeutic modulation of O-GlcNAc. Chem Rev. 2024; 124: 12918-3019. https://doi.org/10.1021/acs.chemrev.4c00417.

[155] Hou C, Li W, Li Y, Ma J. O-GlcNAc informatics: advances and trends. Anal Bioanal Chem. 2025; 417: 895-905. https://doi.org/10.1007/s00216-024-05531-2.