RNA modifications: molecular orchestrators of wound healing

Abstract

Wound healing is a highly coordinated biological process traditionally divided into three phases: inflammatory, proliferative, and remodeling. Diabetes and acute trauma markedly disrupt these stages, resulting in delayed wound closure, persistent inflammation, and impaired tissue regeneration. This review focuses on three trauma-relevant contexts: (i) skin wounds, including diabetic ulcers and burns; (ii) bone fracture healing; and (iii) corneal epithelial and stromal injury. Robust in vivo evidence is synthesized to delineate the mechanistic roles of the four principal ribonucleic acid (RNA) modifications: N⁶-methyladenosine, 5-methylcytosine, N⁷-methylguanosine, and N⁴-acetylcytidine. Additionally, the roles of RNA modification writers, erasers, and readers in regulating macrophage polarization, stem and progenitor cell fate, angiogenesis, lymphangiogenesis, and extracellular matrix remodeling are examined. Evidence across different tissues and wound healing phases is integrated rather than presented descriptively. Methodological limitations are highlighted, and knowledge gaps are identified alongside testable hypotheses. Translational opportunities with direct relevance to burn and trauma management are emphasized. This review aims to integrate mechanistic and translational insights into a coherent framework for therapeutic intervention. By defining how RNA modifications intersect with distinct wound healing phases, concrete therapeutic entry points and delivery strategies relevant to burns and trauma are identified, including topical hydrogels, exosome-based therapies, and bone-targeted nanoparticles. Designs for pragmatic clinical trials and biomarker strategies that enable translation of preclinical findings to patients are also discussed.

Keywords

N6-methyladenosine / 5-methylcytosine / N7-methylguanosine / N4-acetylcytidine / Wound healing / Fracture healing / Corneal repair / Epitranscriptomics

References

[1] Han D, Xu MM. RNA modification in the immune system. Annu Rev Immunol 2023; 41:73-98. https://doi.org/10.1146/annurev-immunol-101921-045401.

[2] Wang C, Hou X, Guan Q, Zhou H, Zhou L, Liu L, et al. RNA modification in cardiovascular disease: implications for therapeutic interventions. Signal Transduct Target Ther 2023; 8:412. https://doi.org/10.1038/s41392-023-01638-7.

[3] Wilkinson E, Cui YH, He YY. Roles of RNA modifications in diverse cellular functions. Front Cell Dev Biol 2022; 10:828683. https://doi.org/10.3389/fcell.2022.828683.

[4] Akhtar J, Lugoboni M, Junion G . m(6)A RNA modification in transcription regulation. Transcription 2021; 12:266-76. https://doi.org/10.1080/21541264.2022.2057177.

[5] Benak D, Kolar F, Zhang L, Devaux Y, Hlavackova M. RNA modification m(6)Am: the role in cardiac biology. Epigenetics 2023; 18:2218771. https://doi.org/10.1080/15592294.2023.2218771.

[6] Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, et al. Modomics: a database of RNA modification pathways. 2017 update. Nucleic Acids Res 46:D303-7. https://doi.org/10.1093/nar/gkx1030.

[7] Patil DP, Pickering BF, Jaffrey SR. Reading m(6)A in the transcriptome: m(6)A-binding proteins. Trends Cell Biol 2018; 28:113-27. https://doi.org/10.1016/j.tcb.2017.10.001.

[8] Shaath H, Vishnubalaji R, Elango R, Kardousha A, Islam Z, Qureshi R, et al. Long non-coding RNA and RNA-binding protein interactions in cancer: experimental and machine learning approaches. Semin Cancer Biol 2022; 86:325-45. https://doi.org/10.1016/j.semcancer.2022.05.013.

[9] Yang Y, Hsu PJ, Chen YS, Yang YG. Dynamic transcriptomic m(6)A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res 2018; 28:616-24. https://doi.org/10.1038/s41422-018-0040-8.

[10] Wu X, Gu R, Tang M, Mu X, He W, Nie X. Elucidating the dual roles of apoptosis and necroptosis in diabetic wound healing: implications for therapeutic intervention. Burns Trauma 2025; 13:tkae061. https://doi.org/10.1093/burnst/tkae061.

[11] Kim HS, Eun JW, Jang SH, Kim JY, Jeong JY. The diverse landscape of RNA modifications in cancer development and progression. Genes Genomics 2025; 47:135-55. https://doi.org/10.1007/s13258-024-01601-y.

[12] Sorg H, Sorg CGG. Skin wound healing: of players, patterns, and processes. Eur Surg Res 2023; 64:141-57. https://doi.org/10.1159/000528271.

[13] Gunage R, Zon LI. Role of RNA modifications in blood development and regeneration. Exp Hematol 2024; 138:104279. https://doi.org/10.1016/j.exphem.2024.104279.

[14] Luo X, Zhu S, Li J, Zeng N, Wang H, Wu Y, et al. Potential genetic therapies based on m6A methylation for skin regeneration: wound healing and scars/keloids. Front Bioeng Biotechnol 2023; 11:1143866. https://doi.org/10.3389/fbioe.2023.1143866.

[15] Zhang Y, Hu W, Li HB. RNA modification-mediated translational control in immune cells. RNA Biol 2023; 20:603-13. https://doi.org/10.1080/15476286.2023.2246256.

[16] Huang X, Zhao Y, Liu D, Gu S, Liu Y, Khoong Y, et al. ALKBH5-mediated m(6)A demethylation fuels cutaneous wound re-epithelialization by enhancing PELI2 mRNA stability. Inflamm Regen 2023; 43:36. https://doi.org/10.1186/s41232-023-00288-0.

[17] Zhou R, Wang Q, Zeng S, Liang Y, Wang D. METTL14-mediated N6-methyladenosine modification of Col17a1/Itg α6/Itg β4 governs epidermal homeostasis. J Dermatol Sci 2023; 112:138-47. https://doi.org/10.1016/j.jdermsci.2023.10.005.

[18] Ju CC, Liu XX, Liu LH, Guo N, Guan LW, Wu JX, et al. Epigenetic modification: a novel insight into diabetic wound healing. Heliyon 2024; 10:e28086. https://doi.org/10.1016/j.heliyon.2024.e28086.

[19] Liu C, Na L . m6A methylation: a new avenue for control of the development of type 2 diabetes mellitus and its complications. Endocr Metab Immune Disord Drug Targets 2024; 25:636-47. https://doi.org/10.2174/0118715303320146240816113924.

[20] Wang B, Zhang J, Li G, Xu C, Yang L, Zhang J, et al. N-acetyltransferase 10 promotes cutaneous wound repair via the NF-κB-IL-6 axis. Cell Death Discov 2023; 9:324. https://doi.org/10.1038/s41420-023-01628-2.

[21] Luo G, Xu W, Chen X, Xu W, Yang S, Wang J, et al. The RNA m5C methylase NSUN2 modulates corneal epithelial wound healing. Invest Ophthalmol Vis Sci 2023; 64:5. https://doi.org/10.1167/iovs.64.3.5.

[22] Zhang Q, Dong L, Gong S, Wang T. Unraveling the landscape of m6A RNA methylation in wound healing and scars. Cell Death Discov 2024; 10:458. https://doi.org/10.1038/s41420-024-02222-w.

[23] Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther 2021; 6:74. https://doi.org/10.1038/s41392-020-00450-x.

[24] Xiong X, Yi C, Peng J. Epitranscriptomics: toward a better understanding of RNA modifications. Genomics Proteomics Bioinformatics 2017; 15:147-53. https://doi.org/10.1016/j.gpb.2017.03.003.

[25] An Y, Duan H. The role of m6A RNA methylation in cancer metabolism. Mol Cancer 2022; 21:14. https://doi.org/10.1186/s12943-022-01500-4.

[26] Huang H, Weng H, Chen J. m(6)A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell 2020; 37:270-88. https://doi.org/10.1016/j.ccell.2020.02.004.

[27] Xu T, He B, Sun H, Xiong M, Nie J, Wang S, et al. Novel insights into the interaction between N6-methyladenosine modification and circular RNA. Mol Ther Nucleic Acids 2022; 27:824-37. https://doi.org/10.1016/j.omtn.2022.01.007.

[28] Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol 2014; 10:93-5. https://doi.org/10.1038/nchembio.1432.

[29] Wang T, Kong S, Tao M, Ju S. The potential role of RNA N6-methyladenosine in cancer progression. Mol Cancer 2020; 19:88. https://doi.org/10.1186/s12943-020-01204-7.

[30] Wang P, Doxtader KA, Nam Y. Structural basis for cooperative function of mettl3 and mettl14 methyltransferases. Mol Cell 2016; 63:306-17. https://doi.org/10.1016/j.molcel.2016.05.041.

[31] Wang X, Huang J, Zou T, Yin P. Human m(6)A writers: two subunits, 2 roles. RNA Biol 2017; 14:300-4. https://doi.org/10.1080/15476286.2017.1282025.

[32] Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell 2017; 169:1187-200. https://doi.org/10.1016/j.cell.2017.05.045.

[33] Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 2014; 24:177-89. https://doi.org/10.1038/cr.2014.3.

[34] Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep 2014; 8:284-96. https://doi.org/10.1016/j.celrep.2014.05.048.

[35] Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, et al. VIRMA mediates preferential m(6)A mRNA methylation in 3′UTR and near stop codon and associates with alternative polyadenylation. Cell Discov 2018; 4:10. https://doi.org/10.1038/s41421-018-0019-0.

[36] Zhang S. Mechanism of N(6)-methyladenosine modification and its emerging role in cancer. Pharmacol Ther 2018; 189:173-83. https://doi.org/10.1016/j.pharmthera.2018.04.011.

[37] Wen J, Lv R, Ma H, Shen H, He C, Wang J, et al. ZC3H13 regulates nuclear RNA m(6)A methylation and mouse embryonic stem cell self-renewal. Mol Cell 2018; 69:1028-38.e6. https://doi.org/10.1016/j.molcel.2018.02.015.

[38] Shima H, Matsumoto M, Ishigami Y, Ebina M, Muto A, Sato Y, et al. S-adenosylmethionine synthesis is regulated by selective N(6)-adenosine methylation and mRNA degradation involving METTL16 and YTHDC1. Cell Rep 2017; 21:3354-63. https://doi.org/10.1016/j.celrep.2017.11.092.

[39] Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 2011; 7:885-7. https://doi.org/10.1038/nchembio.687.

[40] Wei J, Liu F, Lu Z, Fei Q, Ai Y, He PC, et al. Differential m(6)A, m(6)A(m), and m(1)A demethylation mediated by fto in the cell nucleus and cytoplasm. Mol Cell 2018; 71:973-85.e5. https://doi.org/10.1016/j.molcel.2018.08.011.

[41] Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 2013; 49:18-29. https://doi.org/10.1016/j.molcel.2012.10.015.

[42] Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer 2020; 20:303-22. https://doi.org/10.1038/s41568-020-0253-2.

[43] Sun T, Wu R, Ming L. The role of m6A RNA methylation in cancer. Biomed Pharmacother 2019; 112:108613. https://doi.org/10.1016/j.biopha.2019.108613.

[44] Zhang Z, Theler D, Kaminska KH, Hiller M, de la Grange P, Pudimat R, et al. The YTH domain is a novel RNA binding domain. J Biol Chem 2010; 285:14701-10. https://doi.org/10.1074/jbc.M110.104711.

[45] Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol 2018; 20:285-95. https://doi.org/10.1038/s41556-018-0045-z.

[46] Teng PC, Liang Y, Yarmishyn AA, Hsiao YJ, Lin TY, Lin TW, et al. RNA modifications and epigenetics in modulation of lung cancer and pulmonary diseases. Int J Mol Sci 2021;22:22. https://doi.org/10.3390/ijms221910592.

[47] Wang S, Li H, Lian Z, Deng S. The role of RNA modification in HIV-1 infection. Int J Mol Sci 2022; 23:7571. https://doi.org/10.3390/ijms23147571.

[48] Trixl L, Lusser A. The dynamic RNA modification 5-methylcytosine and its emerging role as an epitranscriptomic mark. Wiley Interdiscip Rev RNA 2019; 10:e1510. https://doi.org/10.1002/wrna.1510.

[49] Bohnsack KE, Höbartner C, Bohnsack MT. Eukaryotic 5-methylcytosine (m5C) RNA methyltransferases: mechanisms, cellular functions, and links to disease. Genes (Basel) 2019; 10:102. https://doi.org/10.3390/genes10020102.

[50] Motorin Y, Lyko F, Helm M. 5-methylcytosine in RNA: detection, enzymatic formation and biological functions. Nucleic Acids Res 2010; 38:1415-30. https://doi.org/10.1093/nar/gkp1117.

[51] Shen H, Ontiveros RJ, Owens MC, Liu MY, Ghanty U, Kohli RM, et al. TET-mediated 5-methylcytosine oxidation in tRNA promotes translation. J Biol Chem 2021; 296:100087. https://doi.org/10.1074/jbc.RA120.014226.

[52] Yang H, Wang Y, Xiang Y, Yadav T, Ouyang J, Phoon L, et al. FMRP promotes transcription-coupled homologous recombination via facilitating TET1-mediated m5C RNA modification demethylation. Proc Natl Acad Sci USA 2022; 119:e2116251119. https://doi.org/10.1073/pnas.2116251119.

[53] Yang X, Yang Y, Sun BF, Chen YS, Xu JW, Lai WY, et al. 5-methylcytosine promotes mRNA export-NSUN2 as the methyltransferase and ALYREF as an m(5)C reader. Cell Res 2017; 27:606-25. https://doi.org/10.1038/cr.2017.55.

[54] Zou F, Tu R, Duan B, Yang Z, Ping Z, Song X, et al. Drosophila YBX1 homolog YPS promotes ovarian germ line stem cell development by preferentially recognizing 5-methylcytosine RNAs. Proc Natl Acad Sci USA 2020; 117:3603-9. https://doi.org/10.1073/pnas.1910862117.

[55] Chen Y, Lin H, Miao L, He J. Role of N7-methylguanosine (m(7)G) in cancer. Trends Cell Biol 2022; 32:819-24. https://doi.org/10.1016/j.tcb.2022.07.001.

[56] Zhang M, Song J, Yuan W, Zhang W, Sun Z. Roles of RNA methylation on tumor immunity and clinical implications. Front Immunol 2021; 12:641507. https://doi.org/10.3389/fimmu.2021.641507.

[57] Cheng W, Gao A, Lin H, Zhang W. Novel roles of METTL1/WDR4 in tumor via m(7)G methylation. Mol Ther Oncolytics 2022; 26:27-34. https://doi.org/10.1016/j.omto.2022.05.009.

[58] Zhang LS, Liu C, Ma H, Dai Q, Sun HL, Luo G, et al. Transcriptome-wide mapping of internal N(7)-methylguanosine methylome in mammalian mRNA. Mol Cell 2019; 74:1304-16.e8. https://doi.org/10.1016/j.molcel.2019.03.036.

[59] Létoquart J, Huvelle E, Wacheul L, Bourgeois G, Zorbas C, Graille M, et al. Structural and functional studies of Bud23-Trm112 reveal 18S rRNA N7-G1575 methylation occurs on late 40S precursor ribosomes. Proc Natl Acad Sci USA 2014; 111:E5518-26. https://doi.org/10.1073/pnas.1413089111.

[60] Zorbas C, Nicolas E, Wacheul L, Huvelle E, Heurgué-Hamard V, Lafontaine DL. The human 18S rRNA base methyltransferases DIMT1L and WBSCR22-TRMT112 but not rRNA modification are required for ribosome biogenesis. Mol Biol Cell 2015; 26:2080-95. https://doi.org/10.1091/mbc.E15-02-0073.

[61] Varshney D, Lombardi O, Schweikert G, Dunn S, Suska O, Cowling VH. mRNA cap methyltransferase, RNMT-RAM, promotes RNA pol II-dependent transcription. Cell Rep 2018; 23:1530-42. https://doi.org/10.1016/j.celrep.2018.04.004.

[62] Enroth C, Poulsen LD, Iversen S, Kirpekar F, Albrechtsen A, Vinther J. Detection of internal N7-methylguanosine (m7G) RNA modifications by mutational profiling sequencing. Nucleic Acids Res 2019; 47:e126. https://doi.org/10.1093/nar/gkz736.

[63] Jin G, Xu M, Zou M, Duan S. The processing, gene regulation, biological functions, and clinical relevance of N4-acetylcytidine on RNA: a systematic review. Mol Ther Nucleic Acids 2020; 20:13-24. https://doi.org/10.1016/j.omtn.2020.01.037.

[64] Xie L, Zhong X, Cao W, Liu J, Zu X, Chen L. Mechanisms of NAT10 as ac4C writer in diseases. Mol Ther Nucleic Acids 2023; 32:359-68. https://doi.org/10.1016/j.omtn.2023.03.023.

[65] Arango D, Sturgill D, Alhusaini N, Dillman AA, Sweet TJ, Hanson G, et al. Acetylation of cytidine in mRNA promotes translation efficiency. Cell 2018; 175:1872-86.e24. https://doi.org/10.1016/j.cell.2018.10.030.

[66] Wang K, Zhou LY, Liu F, Lin L, Ju J, Tian PC, et al. PIWI-interacting RNA HAAPIR regulates cardiomyocyte death after myocardial infarction by promoting NAT10-mediated ac(4)C acetylation of Tfec mRNA. Adv Sci (Weinh) 2022; 9:e2106058. https://doi.org/10.1002/advs.202106058.

[67] Bartee D, Nance KD, Meier JL. Site-specific synthesis of N(4)-acetylcytidine in RNA reveals physiological duplex stabilization. J Am Chem Soc 2022; 144:3487-96. https://doi.org/10.1021/jacs.1c11985.

[68] Sleiman S, Dragon F. Recent advances on the structure and function of RNA acetyltransferase Kre33/NAT10. Cells 2019; 8:1035. https://doi.org/10.3390/cells8091035.

[69] Thomas JM, Briney CA, Nance KD, Lopez JE, Thorpe AL, Fox SD, et al. A chemical signature for cytidine acetylation in RNA. J Am Chem Soc 2018; 140:12667-70. https://doi.org/10.1021/jacs.8b06636.

[70] Sharma S, Langhendries JL, Watzinger P, Kötter P, Entian KD, Lafontaine DL. Yeast kre33 and human NAT10 are conserved 18S rRNA cytosine acetyltransferases that modify trnas assisted by the adaptor Tan1/THUMPD1. Nucleic Acids Res 2015; 43:2242-58. https://doi.org/10.1093/nar/gkv075.

[71] Wang T, Li X, Tao Y, Wang X, Li L, Liu J. METTL3-mediated NDUFB5 m6A modification promotes cell migration and mitochondrial respiration to promote the wound healing of diabetic foot ulcer. J Transl Med 2024; 22:643. https://doi.org/10.1186/s12967-024-05463-6.

[72] Li Z, Wang P, Li J, Xie Z, Cen S, Li M, et al. The N(6)-methyladenosine demethylase ALKBH5 negatively regulates the osteogenic differentiation of mesenchymal stem cells through PRMT6. Cell Death Dis 2021; 12:578. https://doi.org/10.1038/s41419-021-03869-4.

[73] Dai Y, Cheng M, Zhang S, Ling R, Wen J, Cheng Y, et al. METTL3-mediated m(6)A RNA modification regulates corneal injury repair. Stem Cells Int 2021; 2021:5512153. https://doi.org/10.1155/2021/5512153.

[74] Wilson SE. Corneal wound healing. Exp Eye Res 2020; 197:108089. https://doi.org/10.1016/j.exer.2020.108089.

[75] Liu J, Zhang Y, Wu Y, Li G, Ji N, Han R, et al. Delivery of m7G methylated Runx2 mRNA by bone-targeted lipid nanoparticle promotes osteoblastic bone formation in senile osteoporosis. Nano Today 2024; 54:102074. https://doi.org/10.1016/j.nantod.2023.102074.

[76] Zhao Y, Kong L, Pei Z, Li F, Li C, Sun X, et al. m7G methyltransferase METTL1 promotes post-ischemic angiogenesis via promoting VEGFA mRNA translation. Front Cell Dev Biol 2021; 9:642080. https://doi.org/10.3389/fcell.2021.642080.

[77] Yu C, Chen Y, Luo H, Lin W, Lin X, Jiang Q, et al. NAT10 promotes vascular remodelling via mRNA ac4C acetylation. Eur Heart J 2025; 46:288-304. https://doi.org/10.1093/eurheartj/ehae707.

[78] Bai Y, Zhang W, Hao L, Zhao Y, Tsai IC, Qi Y, et al. Acetyl-coa-dependent ac(4)C acetylation promotes the osteogenic differentiation of LPS-stimulated BMSCs. Int Immunopharmacol 2024; 133:112124. https://doi.org/10.1016/j.intimp.2024.112124.

[79] Yang W, Li HY, Wu YF, Mi RJ, Liu WZ, Shen X, et al. ac4C acetylation of RUNX2 catalyzed by NAT10 spurs osteogenesis of BMSCs and prevents ovariectomy-induced bone loss. Mol Ther Nucleic Acids 2021; 26:135-47. https://doi.org/10.1016/j.omtn.2021.06.022.

[80] Zhu Z, Xing X, Huang S, Tu Y. NAT10 promotes osteogenic differentiation of mesenchymal stem cells by mediating N4-acetylcytidine modification of gremlin 1. Stem Cells Int 2021; 2021:8833527. https://doi.org/10.1155/2021/8833527.

[81] Baroni A, Buommino E, De Gregorio V, Ruocco E, Ruocco V, Wolf R. Structure and function of the epidermis related to barrier properties. Clin Dermatol 2012; 30:257-62. https://doi.org/10.1016/j.clindermatol.2011.08.007.

[82] Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol 2011; 9:244-53. https://doi.org/10.1038/nrmicro2537.

[83] Nguyen AV, Soulika AM. The dynamics of the skin’s immune system. Int J Mol Sci 2019; 20:1811. https://doi.org/10.3390/ijms20081811.

[84] Nourian Dehkordi A, Mirahmadi Babaheydari F, Chehelgerdi M, Raeisi DS. Skin tissue engineering: wound healing based on stem-cell-based therapeutic strategies. Stem Cell Res Ther 2019; 10:111. https://doi.org/10.1186/s13287-019-1212-2.

[85] Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol 2024; 25:599-616. https://doi.org/10.1038/s41580-024-00715-1.

[86] Burgess JL, Wyant WA, Abdo Abujamra B, Kirsner RS, Jozic I . Diabetic wound-healing science. Medicina (Kaunas) 2021; 57:1072. https://doi.org/10.3390/medicina57101072.

[87] Baltzis D, Eleftheriadou I, Veves A. Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights. Adv Ther 2014; 31:817-36. https://doi.org/10.1007/s12325-014-0140-x.

[88] Deng L, Du C, Song P, Chen T, Rui S, Armstrong DG, et al. The role of oxidative stress and antioxidants in diabetic wound healing. Oxidative Med Cell Longev 2021; 2021:8852759. https://doi.org/10.1155/2021/8852759.

[89] Holl J, Kowalewski C, Zimek Z, Fiedor P, Kaminski A, Oldak T, et al. Chronic diabetic wounds and their treatment with skin substitutes. Cells 2021; 10:655. https://doi.org/10.3390/cells10030655.

[90] Hu SC, Lan CE. High-glucose environment disturbs the physiologic functions of keratinocytes: focusing on diabetic wound healing. J Dermatol Sci 2016; 84:121-7. https://doi.org/10.1016/j.jdermsci.2016.07.008.

[91] Li L, Zhang J, Zhang Q, Zhang D, Xiang F, Jia J, et al. High glucose suppresses keratinocyte migration through the inhibition of p38 MAPK/autophagy pathway. Front Physiol 2019; 10:24. https://doi.org/10.3389/fphys.2019.00024.

[92] Geng X, Li Z, Yang Y. Emerging role of epitranscriptomics in diabetes mellitus and its complications. Front Endocrinol (Lausanne) 2022; 13:907060. https://doi.org/10.3389/fendo.2022.907060.

[93] Ouyang M, Fang J, Wang M, Huang X, Lan J, Qu Y, et al. Advanced glycation end products alter the m(6)A-modified RNA profiles in human dermal fibroblasts. Epigenomics 2022; 14:431-49. https://doi.org/10.2217/epi-2022-0016.

[94] Zhang J, Wang C, Dong X. METTL14-mediated m6A methylation promotes macrophage M2 polarization via YTHDF1-socs1 axis to accelerate skin wound healing. Eur J Med Res 2025; 30:813. https://doi.org/10.1186/s40001-025-03056-7.

[95] Hu X-T, Sui L-M, Pu C-X, Ao L-Q, Yuan M, Deng L, et al. Lactylation-driven METTL3 regulates wound healing by enhancing m6A/HNRNPA2B1/DNMT1 signaling in keratinocytes. Genes & Diseases 2026; 13:101787. https://doi.org/10.1016/j.gendis.2025.101787.

[96] Zhang J, Chen F, Wei W, Ning Q, Zhu D, Fan J, et al. Nr-CWS regulates METTL3-mediated m(6)A modification of CDS2 mRNA in vascular endothelial cells and has prognostic significance. Commun Biol 2024; 7:1348. https://doi.org/10.1038/s42003-024-07047-y.

[97] Liu Y, Liu Z, Tang H, Shen Y, Gong Z, Xie N, et al. The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 facilitates M1 macrophage polarization through the methylation of STAT1 mRNA. Am J Physiol Cell Physiol 2019; 317:C762-75. https://doi.org/10.1152/ajpcell.00212.2019.

[98] Yang Y, Shen F, Huang W, Qin S, Huang JT, Sergi C, et al. Glucose is involved in the dynamic regulation of m6A in patients with type 2 diabetes. J Clin Endocrinol Metab 2019; 104:665-73. https://doi.org/10.1210/jc.2018-00619.

[99] Zheng X, Deng S, Li Y, Luo Z, Gan Z, Zheng Z, et al. Targeting m(6)A demethylase FTO to heal diabetic wounds with ROS-scavenging nanocolloidal hydrogels. Biomaterials 2025; 317:123065. https://doi.org/10.1016/j.biomaterials.2024.123065.

[100] Dong Z, Li S, Huang Y, Chen T, Ding Y, Tan Q. RNA N(6)-methyladenosine demethylase FTO promotes diabetic wound healing through TRIB3-mediated autophagy in an m(6)A-YTHDF2-dependent manner. Cell Death Dis 2025; 16:222. https://doi.org/10.1038/s41419-025-07494-3.

[101] Shen F, Huang W, Huang JT, Xiong J, Yang Y, Wu K, et al. Decreased N(6)-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5. J Clin Endocrinol Metab 2015; 100:E148-54. https://doi.org/10.1210/jc.2014-1893.

[102] Wang J, Wang X, Chen F, Ning Q, Liu Y, Zhu Y, et al. N6-methyladenosine modification of lncCCKAR-5 regulates autophagy in human umbilical cord mesenchymal stem cells by destabilizing LMNA and inhibits diabetic wound healing. J Invest Dermatol 2024; 144:1148-60.e15. https://doi.org/10.1016/j.jid.2023.11.023.

[103] Gu X, Zhang Y, Li D, Cai H, Cai L, Xu Q. N6-methyladenosine demethylase FTO promotes M1 and M2 macrophage activation. Cell Signal 2020; 69:109553. https://doi.org/10.1016/j.cellsig.2020.109553.

[104] Liang D, Lin WJ, Ren M, Qiu J, Yang C, Wang X, et al. m(6)A reader YTHDC1 modulates autophagy by targeting SQSTM1 in diabetic skin. Autophagy 2022; 18:1318-37. https://doi.org/10.1080/15548627.2021.1974175.

[105] Basu A, Kligman LH, Samulewicz SJ, Howe CC. Impaired wound healing in mice deficient in a matricellular protein SPARC (osteonectin, BM-40). BMC Cell Biol 2001; 2:15. https://doi.org/10.1186/1471-2121-2-15.

[106] Wu D, Chen S, Huang D, Huang Z, Zhen N, Zhou Z, et al. Circ-Amotl1 in extracellular vesicles derived from ADSCs improves wound healing by upregulating SPARC translation. Regen Ther 2024; 25:290-301. https://doi.org/10.1016/j.reth.2024.01.005.

[107] Saaristo A, Tammela T, Farkkil¯a A, Kärkkäinen M, Suominen E, Yla-Herttuala S, et al. Vascular endothelial growth factor-C accelerates diabetic wound healing. Am J Pathol 2006; 169:1080-7. https://doi.org/10.2353/ajpath.2006.051251.

[108] Zhou J, Wei T, He Z. ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m(6)A modification to improve wound healing of diabetic foot ulcers. Mol Med 2021; 27:146. https://doi.org/10.1186/s10020-021-00406-z.

[109] Zhi S, Li J, Kong X, Xie X, Zhang Q, Fang G. Insulin-like growth factor 2 mRNA binding protein 2 regulates proliferation, migration, and angiogenesis of keratinocytes by modulating heparanase stability. Bioengineered 2021; 12:11267-76. https://doi.org/10.1080/21655979.2021.2002495.

[110] Wu Y, Zhong JL, Hou N, Sun Y, Ma B, Nisar MF, et al. MicroRNA Let-7b inhibits keratinocyte migration in cutaneous wound healing by targeting IGF2BP2. Exp Dermatol 2017; 26:116-23. https://doi.org/10.1111/exd.13164.

[111] Sun K, Wang W, Wang C, Lao G, Liu D, Mai L, et al. AGEs trigger autophagy in diabetic skin tissues and fibroblasts. Biochem Biophys Res Commun 2016; 471:355-60. https://doi.org/10.1016/j.bbrc.2016.02.020.

[112] Chen Y, Xiang Y, Miao X, Kuai L, Ding X, Ma T, et al. METTL14 promotes IL-6-induced viability, glycolysis and inflammation in HaCaT cells via the m6A modification of TRIM27. J Cell Mol Med 2024; 28:e18085. https://doi.org/10.1111/jcmm.18085.

[113] Lee J, Wu Y, Harada BT, Li Y, Zhao J, He C, et al. N(6)-methyladenosine modification of lncRNA Pvt1 governs epidermal stemness. EMBO J 2021; 40:e106276. https://doi.org/10.15252/embj.2020106276.

[114] Peng J, Zhu H, Ruan B, Duan Z, Cao M. miR-155 promotes m6A modification of SOX2 mRNA through targeted regulation of HIF-1 α and delays wound healing in diabetic foot ulcer in vitro models. J Diabetes Investig 2025; 16:60-71. https://doi.org/10.1111/jdi.14327.

[115] Radzikowska-Büchner E, Łopuszyńska I, Flieger W, Tobiasz M, Maciejewski R, Flieger J. An overview of recent developments in the management of burn injuries. Int J Mol Sci 2023; 24:16357. https://doi.org/10.3390/ijms242216357.

[116] Żwierełło W, Piorun K, Skórka-Majewicz M, Maruszewska A, Antoniewski J, Gutowska I. Burns: classification, pathophysiology, and treatment: a review. Int J Mol Sci 2023; 24:3749. https://doi.org/10.3390/ijms24043749.

[117] Shpichka A, Butnaru D, Bezrukov EA, Sukhanov RB, Atala A, Burdukovskii V, et al. Skin tissue regeneration for burn injury. Stem Cell Res Ther 2019; 10:94. https://doi.org/10.1186/s13287-019-1203-3.

[118] Hall C, Hardin C, Corkins CJ, Jiwani AZ, Fletcher J, Carlsson A, et al. Pathophysiologic mechanisms and current treatments for cutaneous sequelae of burn wounds. Compr Physiol 2017; 8:371-405. https://doi.org/10.1002/cphy.c170016.

[119] Greenhalgh DG. A primer on pigmentation. J Burn Care Res 2015; 36:247-57. https://doi.org/10.1097/bcr.0000000000000224.

[120] Wang Y, Beekman J, Hew J, Jackson S, Issler-Fisher AC, Parungao R, et al. Burn injury: challenges and advances in burn wound healing, infection, pain and scarring. Adv Drug Deliv Rev 2018; 123:3-17. https://doi.org/10.1016/j.addr.2017.09.018.

[121] Xi L, Carroll T, Matos I, Luo JD, Polak L, Pasolli HA, et al. m6A RNA methylation impacts fate choices during skin morphogenesis. Elife 2020; 9:e56980. https://doi.org/10.7554/eLife.56980.

[122] Ran Y, Yan Z, Huang M, Zhou S, Wu F, Wang M, et al. Severe burn injury significantly alters the gene expression and m6A methylation tagging of mRNAs and lncRNAs in human skin. J Pers Med 2023; 13:150. https://doi.org/10.3390/jpm13010150.

[123] Xu Z, Zhu X, Mu S, Fan R, Wang B, Gao W, et al. FTO overexpression expedites wound healing and alleviates depression in burn rats through facilitating keratinocyte migration and angiogenesis via mediating TFPI-2 demethylation. Mol Cell Biochem 2024; 479:325-35. https://doi.org/10.1007/s11010-023-04719-x.

[124] Wang Y, Wang R, Yao B, Hu T, Li Z, Liu Y, et al. TNF-α suppresses sweat gland differentiation of MSCs by reducing FTO-mediated m(6)A-demethylation of Nanog mRNA. Sci China Life Sci 2020; 63:80-91. https://doi.org/10.1007/s11427-019-9826-7.

[125] Liu SY, Wu JJ, Chen ZH, Zou ML, Teng YY, Zhang KWM, et al. The m(6)A RNA modification modulates gene expression and fibrosis-related pathways in hypertrophic scar. Front Cell Dev Biol 2021; 9:748703. https://doi.org/10.3389/fcell.2021.748703.

[126] Young AR. Acute effects of uvr on human eyes and skin. Prog Biophys Mol Biol 2006; 92:80-5. https://doi.org/10.1016/j.pbiomolbio.2006.02.005.

[127] Rowan MP, Cancio LC, Elster EA, Burmeister DM, Rose LF, Natesan S, et al. Burn wound healing and treatment: review and advancements. Crit Care 2015; 19:243. https://doi.org/10.1186/s13054-015-0961-2.

[128] Gabriel VA, McClellan EA, Scheuermann RH. Response of human skin to esthetic scarification. Burns 2014; 40:1338-44. https://doi.org/10.1016/j.burns.2014.01.005.

[129] He L, Liu L, Xu D, Tu Y, Yang C, Zhang M, et al. Deficiency of N6-methyladenosine demethylase ALKBH5 alleviates ultraviolet B radiation-induced chronic actinic dermatitis via regulating pyroptosis. Inflammation 2024; 47:159-72. https://doi.org/10.1007/s10753-023-01901-7.

[130] Zhou X, Li H, Xie Z. METTL3-modified exosomes from adipose-derived stem cells enhance the proliferation and migration of dermal fibroblasts by mediating m6A modification of CCNB1 mRNA. Arch Dermatol Res 2025; 317:418. https://doi.org/10.1007/s00403-025-03896-7.

[131] Wu Y, Xie L, Wang M, Xiong Q, Guo Y, Liang Y, et al. Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis. Nat Commun 2018; 9:4772. https://doi.org/10.1038/s41467-018-06898-4.

[132] Peng J, Zhan Y, Zong Y. METTL3-mediated LINC00657 promotes osteogenic differentiation of mesenchymal stem cells via miR-144-3p/BMPR1B axis. Cell Tissue Res 2022; 388:301-12. https://doi.org/10.1007/s00441-022-03588-y.

[133] Gao X, Wang J, Wang Y, Li W, Pan Z. The m(6)A reader YTHDF1 accelerates the osteogenesis of bone marrow mesenchymal stem cells partly via activation of the autophagy signaling pathway. Stem Cells Int 2023; 2023:5563568. https://doi.org/10.1155/2023/5563568.

[134] Liu T, Zheng X, Wang C, Wang C, Jiang S, Li B, et al. The m(6)A “reader” YTHDF1 promotes osteogenesis of bone marrow mesenchymal stem cells through translational control of ZNF839. Cell Death Dis 2021; 12:1078. https://doi.org/10.1038/s41419-021-04312-4.

[135] Shi D, Liu X, Li X, Li T, Liu J, Wu L. YTH m(6)A RNA-binding protein 1 regulates osteogenesis of MC3T3-E1 cells under hypoxia via translational control of thrombospondin-1. Int J Mol Sci 2023;24:24. https://doi.org/10.3390/ijms24021741.

[136] Chen LS, Zhang M, Chen P, Xiong XF, Liu PQ, Wang HB, et al. The m(6)A demethylase FTO promotes the osteogenesis of mesenchymal stem cells by downregulating PPARG. Acta Pharmacol Sin 2022; 43:1311-23. https://doi.org/10.1038/s41401-021-00756-8.

[137] Bai Y, Jiao X, Hu J, Xue W, Zhou Z, Wang W. WTAP promotes macrophage recruitment and increases VEGF secretion via N6-methyladenosine modification in corneal neovascularization. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166708. https://doi.org/10.1016/j.bbadis.2023.166708.

[138] Wang J, Zhu R, Dong Y, Feng J, Gao J, Wang S, et al. YTHDF3 suppresses declines in corneal epithelial wound healing through upregulating the Wnt/β-catenin signaling pathway and THBS2 expression in diabetic corneas. Int J Biol Macromol 2025; 285:138267. https://doi.org/10.1016/j.ijbiomac.2024.138267.

[139] Jing Y, Li J, Hao P, Xing S, Li X. Silencing METTL3 increases HSP70 expression and alleviates fibrosis in keratocytes. Invest Ophthalmol Vis Sci 2024; 65:9. https://doi.org/10.1167/iovs.65.13.9.

[140] Huang J, Sati S, Murphy C, Spencer CA, Rapp E, Prouty SM, et al. Granulocyte colony stimulating factor promotes scarless tissue regeneration. Cell Rep 2024; 43:114742. https://doi.org/10.1016/j.celrep.2024.114742.

[141] Zomer HD, Trentin AG. Skin wound healing in humans and mice: challenges in translational research. J Dermatol Sci 2018; 90:3-12. https://doi.org/10.1016/j.jdermsci.2017.12.009.

[142] Burgan J, Rahmati M, Lee M, Saiz AM. Innate immune response to bone fracture healing. Bone 2025; 190:117327. https://doi.org/10.1016/j.bone.2024.117327.

[143] Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol 2015; 11:45-54. https://doi.org/10.1038/nrrheum.2014.164.

[144] Bigham-Sadegh A, Oryan A . Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J 2015; 12:238-47. https://doi.org/10.1111/iwj.12231.

[145] Lopas LA, Belkin NS, Mutyaba PL, Gray CF, Hankenson KD, Ahn J. Fractures in geriatric mice show decreased callus expansion and bone volume. Clin Orthop Relat Res 2014; 472:3523-32. https://doi.org/10.1007/s11999-014-3829-x.

[146] Saul D, Khosla S. Fracture healing in the setting of endocrine diseases, aging, and cellular senescence. Endocr Rev 2022; 43:984-1002. https://doi.org/10.1210/endrev/bnac008.

[147] Mi B, Xiong Y, Yan C, Chen L, Xue H, Panayi AC, et al. Methyltransferase-like 3-mediated N6-methyladenosine modification of miR-7212-5p drives osteoblast differentiation and fracture healing. J Cell Mol Med 2020; 24:6385-96. https://doi.org/10.1111/jcmm.15284.

[148] Li Y, Meng L, Zhao B. The roles of N6-methyladenosine methylation in the regulation of bone development, bone remodeling and osteoporosis. Pharmacol Ther 2022; 238:108174. https://doi.org/10.1016/j.pharmthera.2022.108174.

[149] Yu J, Shen L, Liu Y, Ming H, Zhu X, Chu M, et al. The m6A methyltransferase METTL3 cooperates with demethylase ALKBH5 to regulate osteogenic differentiation through NF-κB signaling. Mol Cell Biochem 2020; 463:203-10. https://doi.org/10.1007/s11010-019-03641-5.

[150] Liu J, Chen M, Ma L, Dang X, Du G. piRNA-36741 regulates BMP2-mediated osteoblast differentiation via METTL3 controlled m6A modification. Aging (Albany NY) 2021; 13:23361-75. https://doi.org/10.18632/aging.203630.

[151] Wang J, Li X, Qubi W, Li Y, Wang Y, Wang Y, et al. The important role of m6A-modified circrnas in the differentiation of intramuscular adipocytes in goats based on merip sequencing analysis. Int J Mol Sci 2023; 24:4817. https://doi.org/10.3390/ijms24054817.

[152] Meyer KD. Dart-seq: An antibody-free method for global m6a detection. Nat Methods 2019; 16:1275-80. https://doi.org/10.1038/s41592-019-0570-0.

[153] Shu X, Cao J, Cheng M, Xiang S, Gao M, Li T, et al. A metabolic labeling method detects m(6)A transcriptome-wide at single base resolution. Nat Chem Biol 2020; 16:887-95. https://doi.org/10.1038/s41589-020-0526-9.

[154] Wang W, Qiao SC, Wu XB, Sun B, Yang JG, Li X, et al. Circ_0008542 in osteoblast exosomes promotes osteoclast-induced bone resorption through m6A methylation. Cell Death Dis 2021; 12:628. https://doi.org/10.1038/s41419-021-03915-1.

[155] Tian S, Li YL, Wang J, Dong RC, Wei J, Ma Y, et al. Chinese ecliptae herba (eclipta prostrata (L.) L.) extract and its component wedelolactone enhances osteoblastogenesis of bone marrow mesenchymal stem cells via targeting METTL3-mediated m6A RNA methylation. J Ethnopharmacol 2023; 312:116433. https://doi.org/10.1016/j.jep.2023.116433.

[156] Jiang W, Zhu P, Huang F, Zhao Z, Zhang T, An X, et al. The RNA methyltransferase METTL3 promotes endothelial progenitor cell angiogenesis in mandibular distraction osteogenesis via the PI3K/AKT pathway. Front Cell Dev Biol 2021; 9:720925. https://doi.org/10.3389/fcell.2021.720925.

[157] Yan G, Yuan Y, He M, Gong R, Lei H, Zhou H, et al. m(6)A methylation of precursor-miR-320/RUNX2 controls osteogenic potential of bone marrow-derived mesenchymal stem cells. Mol Ther Nucleic Acids 2020; 19:421-36. https://doi.org/10.1016/j.omtn.2019.12.001.

[158] Lei H, He M, He X, Li G, Wang Y, Gao Y, et al. METTL3 induces bone marrow mesenchymal stem cells osteogenic differentiation and migration through facilitating M1 macrophage differentiation. Am J Transl Res 2021; 13:4376-88. PMID: 34150020.

[159] Tian C, Huang Y, Li Q, Feng Z, Xu Q. METTL3 regulates osteogenic differentiation and alternative splicing of VEGFA in bone marrow mesenchymal stem cells. Int J Mol Sci 2019; 20:551. https://doi.org/10.3390/ijms20030551.

[160] Zhang Y, Gu X, Li D, Cai L, Xu Q. METTL3 regulates osteoblast differentiation and inflammatory response via smad signaling and MAPK signaling. Int J Mol Sci 2019; 21:199. https://doi.org/10.3390/ijms21010199.

[161] Li D, Cai L, Meng R, Feng Z, Xu Q. METTL3 modulates osteoclast differentiation and function by controlling RNA stability and nuclear export. Int J Mol Sci 2020; 21:1660. https://doi.org/10.3390/ijms21051660.

[162] Wang Y, Yu X, Sun F, Fu Y, Hu T, Shi Q, et al. METTL14 mediates Glut3 m6A methylation to improve osteogenesis under oxidative stress condition. Redox Rep 2025; 30:2435241. https://doi.org/10.1080/13510002.2024.2435241.

[163] He M, Lei H, He X, Liu Y, Wang A, Ren Z, et al. METTL14 regulates osteogenesis of bone marrow mesenchymal stem cells via inducing autophagy through m6A/IGF2BPs/Beclin-1 signal axis. Stem Cells Transl Med 2022; 11:987-1001. https://doi.org/10.1093/stcltm/szac049.

[164] Zhang X, Wang Y, Zhao H, Han X, Zhao T, Qu P, et al. Extracellular vesicle-encapsulated miR-22-3p from bone marrow mesenchymal stem cell promotes osteogenic differentiation via FTO inhibition. Stem Cell Res Ther 2020; 11:227. https://doi.org/10.1186/s13287-020-01707-6.

[165] Zhou J, Zhu Y, Ai D, Zhou M, Li H, Li G, et al. Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N(6)-methyladenosine modification of sclerostin. J Transl Med 2023; 21:781. https://doi.org/10.1186/s12967-023-04630-5.

[166] Shen X, Lan C, Lin Y, Zhang F, Zhang Y, Chen M, et al. Suppression of TLR4 prevents diabetic bone loss by regulating FTO-mediated m(6)A modification. Int Immunopharmacol 2023; 122:110510. https://doi.org/10.1016/j.intimp.2023.110510.

[167] Li Y, Yang F, Gao M, Gong R, Jin M, Liu T, et al. miR-149-3p regulates the switch between adipogenic and osteogenic differentiation of BMSCs by targeting FTO. Mol Ther Nucleic Acids 2019; 17:590-600. https://doi.org/10.1016/j.omtn.2019.06.023.

[168] Lai A, Sun J, Dai Z, Guo L, Tao D, Li H, et al. Unraveling IGFBP3-mediated m6A modification in fracture healing. Pathol Res Pract 2024; 255:155220. https://doi.org/10.1016/j.prp.2024.155220.

[169] Eguchi K, Akiba Y, Akiba N, Nagasawa M, Cooper LF, Uoshima K. Insulin-like growth factor binding protein-3 suppresses osteoblast differentiation via bone morphogenetic protein-2. Biochem Biophys Res Commun 2018; 507:465-70. https://doi.org/10.1016/j.bbrc.2018.11.065.

[170] Kim JH, Yoon SM, Song SU, Park SG, Kim WS, Park IG, et al. Hypoxia suppresses spontaneous mineralization and osteogenic differentiation of mesenchymal stem cells via IGFBP3 up-regulation. Int J Mol Sci 2016; 17:1389. https://doi.org/10.3390/ijms17091389.

[171] Musto A, Navarra A, Vocca A, Gargiulo A, Minopoli G, Romano S, et al. miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis. Cell Death Differ 2015; 22:1047-57. https://doi.org/10.1038/cdd.2014.198.

[172] Yang X, Lin Y, Chen T, Hu W, Li P, Qiu X, et al. YTHDF1 enhances chondrogenic differentiation by activating the Wnt/β-catenin signaling pathway. Stem Cells Dev 2023; 32:115-30. https://doi.org/10.1089/scd.2022.0216.

[173] Sridhar MS. Anatomy of cornea and ocular surface. Indian J Ophthalmol 2018; 66:190-4. https://doi.org/10.4103/ijo.IJO_646_17.

[174] Brockmann T, Walckling M, Brockmann C, Fuchsluger TMA, Pleyer U. Corneal wound healing-pathophysiology and principles. Ophthalmologe 2021; 118:1167-77. https://doi.org/10.1007/s00347-021-01423-3.

[175] Brockmann T, Simon A, Brockmann C, Fuchsluger TA, Pleyer U, Walckling M. Corneal wound healing-pharmacological treatment. Ophthalmologie 2024; 121:245-58. https://doi.org/10.1007/s00347-024-02021-9.

[176] Ljubimov AV, Saghizadeh M. Progress in corneal wound healing. Prog Retin Eye Res 2015; 49:17-45. https://doi.org/10.1016/j.preteyeres.2015.07.002.

[177] Vaidyanathan U, Hopping GC, Liu HY, Somani AN, Ronquillo YC, Hoopes PC, et al. Persistent corneal epithelial defects: a review article. Med Hypothesis Discov Innov Ophthalmol 2019; 8:163-76. PMID: 31598519.

[178] Gao JF, Zhang L. The role of N6-methyladenosine (m6A) in eye diseases. Mol Biol Rep 2021; 48:6145-50. https://doi.org/10.1007/s11033-021-06596-3.

[179] Yao MD, Jiang Q, Ma Y, Liu C, Zhu CY, Sun YN, et al. Role of METTL3-dependent N(6)-methyladenosine mRNA modification in the promotion of angiogenesis. Mol Ther 2020; 28:2191-202. https://doi.org/10.1016/j.ymthe.2020.07.022.

[180] Luo G, Zhao Y, Reinach PS, Yan D. m6A RNA modification regulates corneal epithelial wound healing. Invest Ophthalmol Vis Sci 2019; 60:3438-8.

[181] Fei X, Cai Y, Lin F, Huang Y, Liu T, Liu Y. Amniotic fluid mesenchymal stem cells repair mouse corneal cold injury by promoting mRNA N4-acetylcytidine modification and ETV4/JUN/CCND2 signal axis activation. Hum Cell 2021; 34:86-98. https://doi.org/10.1007/s13577-020-00442-7.

[182] Blanco S, Kurowski A, Nichols J, Watt FM, Benitah SA, Frye M. The RNA-methyltransferase misu (NSun2) poises epidermal stem cells to differentiate. PLoS Genet 2011; 7:e1002403. https://doi.org/10.1371/journal.pgen.1002403.

[183] Li YJ, Guo Q, Ye MS, Cai G, Xiao WF, Deng S, et al. YBX1 promotes type H vessel-dependent bone formation in an m5C-dependent manner. JCI Insight 2024; 9:e172345. https://doi.org/10.1172/jci.insight.172345.

[184] Tu L, Gu S, Xu R, Yang E, Huang X, Liang H, et al. ALKBH3-mediated m(1)A demethylation of METTL3 endows pathological fibrosis: interplay between m(1)A and m(6)A RNA methylation. Adv Sci (Weinh) 2025; 12:e2417067. https://doi.org/10.1002/advs.202417067.

[185] Sun Y, Ju Y, Fang B. Exosomes from human adipose-derived mesenchymal stromal/stem cells accelerate angiogenesis in wound healing: implication of the EGR-1/lncRNA-SENCR/DKC1/VEGF-A axis. Hum Cell 2022; 35:1375-90. https://doi.org/10.1007/s13577-022-00732-2.

[186] Wang W, Chen L, Zhang Y, Wang H, Dong D, Zhu J, et al. Adipose-derived stem cells enriched with therapeutic mRNA TGF-β3 and IL-10 synergistically promote scarless wound healing in preclinical models. Bioeng Transl Med 2024; 9:e10620. https://doi.org/10.1002/btm2.10620.

[187] Zaccara S, Ries RJ, Jaffrey SR. Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol 2019; 20:608-24. https://doi.org/10.1038/s41580-019-0168-5.

[188] Zhao X, Wu H, Guo B, Dong R, Qiu Y, Ma PX. Antibacterial anti-oxidant electroactive injectable hydrogel as self-healing wound dressing with hemostasis and adhesiveness for cutaneous wound healing. Biomaterials 2017; 122:34-47. https://doi.org/10.1016/j.biomaterials.2017.01.011.

[189] Wang C, Wang M, Xu T, Zhang X, Lin C, Gao W, et al. Engineering bioactive self-healing antibacterial exosomes hydrogel for promoting chronic diabetic wound healing and complete skin regeneration. Theranostics 2019; 9:65-76. https://doi.org/10.7150/thno.29766.

[190] Welsh JA, Goberdhan DCI, O’Driscoll L, Buzas EI, Blenkiron C, Bussolati B, et al. Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J Extracell Vesicles 2024; 13:e12404. https://doi.org/10.1002/jev2.12404.

[191] Lener T, Gimona M, Aigner L, Börger V, Buzas E, Camussi G, et al. Applying extracellular vesicles based therapeutics in clinical trials-an ISEV position paper. J Extracell Vesicles 2015; 4:30087. https://doi.org/10.3402/jev.v4.30087.

[192] Larrieu D, Viré E, Robson S, Breusegem SY, Kouzarides T, Jackson SP. Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the transportin-1 nuclear import pathway. Sci Signal 2018; 11:eaar5401. https://doi.org/10.1126/scisignal.aar5401.

[193] Hou X, Zaks T, Langer R, Dong Y. Lipid nanoparticles for mRNA delivery. Nat Rev Mater 2021; 6:1078-94. https://doi.org/10.1038/s41578-021-00358-0.

[194] Cullis PR, Hope MJ. Lipid nanoparticle systems for enabling gene therapies. Mol Ther 2017; 25:1467-75. https://doi.org/10.1016/j.ymthe.2017.03.013.

[195] Wu Y, Sun B, Tang Y, Shen A, Lin Y, Zhao X, et al. Bone targeted nano-drug and nano-delivery. Bone Research 2024; 12:51. https://doi.org/10.1038/s41413-024-00356-2.

[196] Song SJ, Yoon HK, Han SH, Park HK, Lee IS. Wedge tibial shaft fractures treated with interlocking IM nailing. J Musculoskelet Trauma 2006; 19:322-8. https://doi.org/10.12671/jkfs.2006.19.3.322.

[197] Zhang H, Wu S, Chen W, Hu Y, Geng Z, Su J. Bone/cartilage targeted hydrogel: strategies and applications. Bioact Mater 2023; 23:156-69. https://doi.org/10.1016/j.bioactmat.2022.10.028.

[198] Abtahi MA, Beheshtnejad AH, Latifi G, Akbari-Kamrani M, Ghafarian S, Masoomi A, et al. Corneal epithelial thickness mapping: a major review. J Ophthalmol 2024; 2024:6674747. https://doi.org/10.1155/2024/6674747.

[199] Dupps WJ Jr, Wilson SE. Biomechanics and wound healing in the cornea. Exp Eye Res 2006; 83:709-20. https://doi.org/10.1016/j.exer.2006.03.015.

[200] Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 2004; 113:1040-50. https://doi.org/10.1172/jci20465.

[201] Salabarria AC, Braun G, Heykants M, Koch M, Reuten R, Mahabir E, et al. Local VEGF-A blockade modulates the microenvironment of the corneal graft bed. Am J Transplant 2019; 19:2446-56. https://doi.org/10.1111/ajt.15331.

[202] Nicholas MP, Mysore N . Corneal neovascularization. Exp Eye Res 2021; 202:108363. https://doi.org/10.1016/j.exer.2020.108363.

[203] Zeng Z, Li S, Ye X, Wang Y, Wang Q, Chen Z, et al. Genome editing VEGFA prevents corneal neovascularization in vivo. Adv Sci (Weinh) 2024; 11:e2401710. https://doi.org/10.1002/advs.202401710.

[204] Tang J, Chen S, Jia G. Detection, regulation, and functions of RNA N(6)-methyladenosine modification in plants. Plant Commun 2023; 4:100546. https://doi.org/10.1016/j.xplc.2023.100546.

[205] Manschot C, Laber E, Davidian M. Interim monitoring of sequential multiple assignment randomized trials using partial information. Biometrics 2023; 79:2881-94. https://doi.org/10.1111/biom.13854.

[206] Xiao B, Ackun-Farmmer MA, Adjei-Sowah E, Liu Y, Chandrasiri I, Benoit DSW. Advancing bone-targeted drug delivery: leveraging biological factors and nanoparticle designs to improve therapeutic efficacy. ACS Biomater Sci Eng 2024; 10:2224-34. https://doi.org/10.1021/acsbiomaterials.3c01022.

[207] Sridharan K, Sivaramakrishnan G. Growth factors for diabetic foot ulcers: mixed treatment comparison analysis of randomized clinical trials. Br J Clin Pharmacol 2018; 84:434-44. https://doi.org/10.1111/bcp.13470.

[208] Miceli RT, Chen TY, Nose Y, Tichkule S, Brown B, Fullard JF, et al. Extracellular vesicles, RNA sequencing, and bioinformatic analyses: challenges, solutions, and recommendations. J Extracell Vesicles 2024; 13:e70005. https://doi.org/10.1002/jev2.70005.

[209] Liu C, Cheng C, Cheng K, Gao AS, Li Q, Atala A, et al. Precision exosome engineering for enhanced wound healing and scar revision. J Transl Med 2025; 23:578. https://doi.org/10.1186/s12967-025-06578-0.

[210] Blackburn B, Dutra BAL, Hammoud B, Scarcelli G, Dupps WJ, Randleman JB, et al. Riboflavin-UV crosslinking of the cornea: wound healing and biomechanics. Exp Eye Res 2025; 254:110321. https://doi.org/10.1016/j.exer.2025.110321.

[211] Yun H, Yee MB, Lathrop KL, Kinchington PR, Hendricks RL, St Leger AJ. Production of the cytokine VEGF-A by CD4(+) T and myeloid cells disrupts the corneal nerve landscape and promotes herpes stromal keratitis. Immunity 2020; 53:1050-62.e5. https://doi.org/10.1016/j.immuni.2020.10.013.

[212] Michiels H, Sotto C, Vandebosch A, Vansteelandt S. A novel estimand to adjust for rescue treatment in randomized clinical trials. Stat Med 2021; 40:2257-71. https://doi.org/10.1002/sim.8901.

[213] Fülöp T, Nemes R, Mészáros T, Urbanics R, Kok RJ, Jackman JA, et al. Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated spions in the pig carpa model: correlation with physicochemical features and clinical information. J Control Release 2018; 270:268-74. https://doi.org/10.1016/j.jconrel.2017.11.043.

[214] Food US, Administration D.Chemistry, manufacturing, and control (CMC) information for human gene therapy investigational new drug applications (INDs). Guidance for Industry 2020. Available from: https://www.fda.gov/media/113760/download.

[215] European Medicines Agency . Guideline on quality, non-clinical and clinical aspects of gene therapy medicinal products EMA/CAT/80183/2014, 22 March. 2018. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-non-clinical-and-clinical-aspects-gene-therapy-medicinal-products_en.pdf.

[216] Rotte A. Development of cell and gene therapies for clinical use in the us and eu: summary of regulatory guidelines. Curr Gene Ther 2025; 25:10-21. https://doi.org/10.2174/0115665232306205240419091414.

[217] Hu L, Liu S, Peng Y, Ge R, Su R, Senevirathne C, et al. m(6)A RNA modifications are measured at single-base resolution across the mammalian transcriptome. Nat Biotechnol 2022; 40:1210-9. https://doi.org/10.1038/s41587-022-01243-z.

[218] Tegowski M, Flamand MN, Meyer KD. Scdart-seq reveals distinct m(6)A signatures and mRNA methylation heterogeneity in single cells. Mol Cell 2022; 82:868-78.e10. https://doi.org/10.1016/j.molcel.2021.12.038.

[219] Zeng H, Huang J, Ren J, Wang CK, Tang Z, Zhou H, et al. Spatially resolved single-cell translatomics at molecular resolution. Science 2023; 380:eadd3067. https://doi.org/10.1126/science.add3067.

[220] Cruciani S, Novoa EM. The new era of single-molecule RNA modification detection through nanopore base-calling models. Nat Rev Mol Cell Biol 2026; 27:10-8. https://doi.org/10.1038/s41580-025-00896-3.

[221] Fang R, Xia C, Close JL, Zhang M, He J, Huang Z, et al. Conservation and divergence of cortical cell organization in human and mouse revealed by merfish. Science 2022; 377:56-62. https://doi.org/10.1126/science.abm1741.

[222] Gasek NS, Yan P, Zhu J, Purushothaman KR, Kim T, Wang L, et al. Clearance of p21 highly expressing senescent cells accelerates cutaneous wound healing. Nat Aging 2025; 5:21-7. https://doi.org/10.1038/s43587-024-00755-4.

[223] Griffin M, Guo JL, Parker JBL, Kuhnert M, Li DJ, Valencia C, et al. Multi-omic analysis reveals retinoic acid molecular drivers for dermal fibrosis and regenerative repair in the skin. Cell Stem Cell 2025; 32:1421-37.e6. https://doi.org/10.1016/j.stem.2025.07.010.