{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T02:21:27Z","timestamp":1783736487503,"version":"3.55.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"Enshi Innovation and Development Joint Fund","award":["JCZRLH202500476"],"award-info":[{"award-number":["JCZRLH202500476"]}]},{"name":"Industry-University-Research Innovation Fund for Chinese Universities","award":["2021ITA03006"],"award-info":[{"award-number":["2021ITA03006"]}]},{"name":"Online Education and Teaching Research Project for Graduate Students in Chinese Medicine","award":["B YXC2024-02-03 10"],"award-info":[{"award-number":["B YXC2024-02-03 10"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-26306-4","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T12:44:53Z","timestamp":1764247493000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Multi-omics and experimental validation identify methylation-related genes and METTL16 as key regulators in diabetic foot ulcer pathogenesis"],"prefix":"10.1038","volume":"15","author":[{"given":"Yilan","family":"Tong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sicheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanyong","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingquan","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"26306_CR1","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/S0140-6736(23)01301-6","volume":"402","author":"KL Ong","year":"2023","unstructured":"Ong, K. L. et al. Global, regional, and National burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the global burden of disease study 2021. Lancet 402, 203\u2013234 (2023).","journal-title":"Lancet"},{"key":"26306_CR2","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1002\/med.22020","volume":"44","author":"F Wang","year":"2024","unstructured":"Wang, F. et al. Recent advances in the adjunctive management of diabetic foot ulcer: focus on noninvasive technologies. Med. Res. Rev. 44, 1501\u20131544 (2024).","journal-title":"Med. Res. Rev."},{"key":"26306_CR3","doi-asserted-by":"crossref","unstructured":"An, Y. & Duan, H. The role of m6A RNA methylation in cancer metabolism. Mol Cancer 21(1), 14 (2022).","DOI":"10.1186\/s12943-022-01500-4"},{"key":"26306_CR4","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1080\/15548627.2021.1974175","volume":"18","author":"D Liang","year":"2022","unstructured":"Liang, D. et al. m6A reader YTHDC1 modulates autophagy by targeting SQSTM1 in diabetic skin. Autophagy 18, 1318\u20131337 (2022).","journal-title":"Autophagy"},{"key":"26306_CR5","doi-asserted-by":"crossref","unstructured":"Zheng, X. et al. Targeting m6A demethylase FTO to heal diabetic wounds with ROS-scavenging nanocolloidal hydrogels. Biomaterials 317, 123065 (2025).","DOI":"10.1016\/j.biomaterials.2024.123065"},{"key":"26306_CR6","doi-asserted-by":"crossref","unstructured":"Zhou, J., Wei, T. & He, Z. ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers. Molecular Medicine 27, 146 (2021).","DOI":"10.1186\/s10020-021-00406-z"},{"key":"26306_CR7","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.tig.2023.10.003","volume":"40","author":"MI Conte","year":"2024","unstructured":"Conte, M. I. & Fuentes-Trillo, A. Dom\u00ednguez Conde, C. Opportunities and tradeoffs in single-cell transcriptomic technologies. Trends Genet. 40, 83\u201393 (2024).","journal-title":"Trends Genet."},{"key":"26306_CR8","doi-asserted-by":"crossref","unstructured":"Huang, F. et al. Microenvironment-Based diabetic foot ulcer nanomedicine. Advanced Science 10, e2203308 (2023).","DOI":"10.1002\/advs.202203308"},{"key":"26306_CR9","doi-asserted-by":"crossref","unstructured":"Sawaya, A. P. et al. Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Nat Commun 11(1), 678 (2020).","DOI":"10.1038\/s41467-020-18276-0"},{"key":"26306_CR10","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1016\/j.jid.2017.11.038","volume":"138","author":"HA Ramirez","year":"2018","unstructured":"Ramirez, H. A. et al. Staphylococcus aureus triggers induction of miR-15B-5P to diminish DNA repair and deregulate inflammatory response in diabetic foot ulcers. J. Invest. Dermatology. 138, 1187\u20131196 (2018).","journal-title":"J. Invest. Dermatology"},{"key":"26306_CR11","doi-asserted-by":"crossref","unstructured":"Theocharidis, G. et al. Single cell transcriptomic landscape of diabetic foot ulcers. Nat Commun 13(1), 181  (2022).","DOI":"10.1038\/s41467-021-27801-8"},{"key":"26306_CR12","doi-asserted-by":"crossref","unstructured":"Zhang, Y. et al. Identification of molecular subtypes and a prognostic signature based on m6A\/m5C\/m1A-related genes in lung adenocarcinoma. Sci Rep 14(1), 7543 (2024).","DOI":"10.1038\/s41598-024-57910-5"},{"key":"26306_CR13","doi-asserted-by":"crossref","unstructured":"ren, M. et al. Exploration and validation of a combined hypoxia and m6A\/m5C\/m1A regulated gene signature for prognosis prediction of liver cancer. BMC Genomics 24(1), 776 (2023).","DOI":"10.1186\/s12864-023-09876-3"},{"key":"26306_CR14","doi-asserted-by":"crossref","unstructured":"Liu, M. et al. Prognostic model and CeRNA network of m7G- and radiosensitivity-related genes in hepatocellular carcinoma. Heliyon 10(9), e29925 (2024).","DOI":"10.1016\/j.heliyon.2024.e29925"},{"key":"26306_CR15","doi-asserted-by":"crossref","unstructured":"Li, Y., Ge, X., Peng, F., Li, W. & Li, J. J. Exaggerated false positives by popular differential expression methods when analyzing human population samples. Genome Biol 23(1), 79 (2022).","DOI":"10.1186\/s13059-022-02648-4"},{"key":"26306_CR16","doi-asserted-by":"crossref","unstructured":"Wu, T. et al. ClusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation 2(3), 100141 (2021).","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"26306_CR17","doi-asserted-by":"crossref","unstructured":"H\u00e4nzelmann, S., Castelo, R. & Guinney, J. G. S. V. A. Gene set variation analysis for microarray and RNA-Seq data. BMC Bioinformatics 14, 7 (2013).","DOI":"10.1186\/1471-2105-14-7"},{"key":"26306_CR18","doi-asserted-by":"publisher","first-page":"D587","DOI":"10.1093\/nar\/gkac963","volume":"51","author":"M Kanehisa","year":"2023","unstructured":"Kanehisa, M., Furumichi, M., Sato, Y. & Kawashima, M. Ishiguro-Watanabe, M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 51, D587\u2013D592 (2023).","journal-title":"Nucleic Acids Res."},{"key":"26306_CR19","doi-asserted-by":"publisher","first-page":"D330","DOI":"10.1093\/nar\/gky1055","volume":"47","author":"S Carbon","year":"2019","unstructured":"Carbon, S. et al. The gene ontology resource: 20 years and still going strong. Nucleic Acids Res. 47, D330\u2013D338 (2019).","journal-title":"Nucleic Acids Res."},{"key":"26306_CR20","doi-asserted-by":"publisher","first-page":"3709","DOI":"10.1038\/s41467-021-24110-y","volume":"12","author":"CC Deng","year":"2021","unstructured":"Deng, C. C. et al. Single-cell RNA-seq reveals fibroblast heterogeneity and increased mesenchymal fibroblasts in human fibrotic skin diseases. Nat. Commun. 12, 3709 (2021).","journal-title":"Nat. Commun."},{"key":"26306_CR21","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1038\/s41596-024-01045-4","volume":"20","author":"S Jin","year":"2025","unstructured":"Jin, S., Plikus, M. V. & Nie, Q. CellChat for systematic analysis of cell\u2013cell communication from single-cell transcriptomics. Nat. Protoc. 20, 180\u2013219 (2025).","journal-title":"Nat. Protoc."},{"key":"26306_CR22","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/nmeth.4402","volume":"14","author":"X Qiu","year":"2017","unstructured":"Qiu, X. et al. Reversed graph embedding resolves complex single-cell trajectories. Nat. Methods. 14, 979\u2013982 (2017).","journal-title":"Nat. Methods"},{"key":"26306_CR23","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1038\/nmeth.4463","volume":"14","author":"S Aibar","year":"2017","unstructured":"Aibar, S. et al. Single-cell regulatory network inference and clustering. Nat. Methods. 14, 1083\u20131086 (2017).","journal-title":"Nat. Methods"},{"key":"26306_CR24","doi-asserted-by":"crossref","unstructured":"Fan, C. et al. IrGSEA: the integration of single-cell rank-based gene set enrichment analysis. Brief Bioinform 25(4), bbae243 (2024).","DOI":"10.1093\/bib\/bbae243"},{"key":"26306_CR25","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1021\/acs.accounts.0c00864","volume":"54","author":"M Chang","year":"2021","unstructured":"Chang, M. & Nguyen, T. T. Strategy for treatment of infected diabetic foot ulcers. Acc. Chem. Res. 54, 1080\u20131093 (2021).","journal-title":"Acc. Chem. Res."},{"key":"26306_CR26","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1038\/s41586-022-04898-5","volume":"607","author":"S Delaunay","year":"2022","unstructured":"Delaunay, S. et al. Mitochondrial RNA modifications shape metabolic plasticity in metastasis. Nature 607, 593\u2013603 (2022).","journal-title":"Nature"},{"key":"26306_CR27","doi-asserted-by":"crossref","unstructured":"Wu, X. et al. The m6A methyltransferase METTL3 drives neuroinflammation and neurotoxicity through stabilizing BATF mRNA in microglia. Cell Death Differ 32(1), 100\u2013117 (2024).","DOI":"10.1038\/s41418-024-01329-y"},{"key":"26306_CR28","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/s41556-021-00835-2","volume":"24","author":"R Su","year":"2022","unstructured":"Su, R. et al. METTL16 exerts an m6A-independent function to facilitate translation and tumorigenesis. Nat. Cell. Biol. 24, 205\u2013216 (2022).","journal-title":"Nat. Cell. Biol."},{"key":"26306_CR29","doi-asserted-by":"crossref","unstructured":"Liu, N., Zhang, J., Chen, W., Ma, W. & Wu, T. The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression. Journal Experimental Clin. Cancer Research 42(1), 263 (2023).","DOI":"10.1186\/s13046-023-02844-5"},{"key":"26306_CR30","doi-asserted-by":"publisher","first-page":"4128","DOI":"10.7150\/ijbs.95375","volume":"20","author":"J Wu","year":"2024","unstructured":"Wu, J. et al. METTL16 promotes stability of SYNPO2L mRNA and leading to cancer cell lung metastasis by secretion of COL10A1 and attract the cancer-Associated fibroblasts. Int. J. Biol. Sci. 20, 4128\u20134145 (2024).","journal-title":"Int. J. Biol. Sci."},{"key":"26306_CR31","doi-asserted-by":"crossref","unstructured":"Wu, F. et al. Dynamic alteration profile and new role of RNA m6A methylation in replicative and H2O2-Induced premature senescence of human embryonic lung fibroblasts. Int J. Mol. Sci 23(16), 9271 (2022).","DOI":"10.3390\/ijms23169271"},{"key":"26306_CR32","doi-asserted-by":"crossref","unstructured":"Lou, Y. et al. Biomimetic rhCOL17-P334 conjugate for enhanced wound healing. Advanced Materials 37(15), e2417980 (2025).","DOI":"10.1002\/adma.202417980"},{"key":"26306_CR33","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.addr.2018.04.011","volume":"146","author":"H Pratsinis","year":"2019","unstructured":"Pratsinis, H., Mavrogonatou, E. & Kletsas, D. Scarless wound healing: from development to senescence. Adv. Drug Deliv Rev. 146, 325\u2013343 (2019).","journal-title":"Adv. Drug Deliv Rev."},{"key":"26306_CR34","doi-asserted-by":"crossref","unstructured":"Srivastava, P., Sondak, T., Sivashanmugam, K. & Kim, K. S. A Review of Immunomodulatory Reprogramming by Probiotics in Combating Chronic and Acute Diabetic Foot Ulcers (DFUs). Pharmaceutics 14(11), 2436 (2022).","DOI":"10.3390\/pharmaceutics14112436"},{"key":"26306_CR35","doi-asserted-by":"publisher","unstructured":"Tang, R. et al. Stromal Stiffness-Regulated IGF2BP2 in Pancreatic Cancer Drives Immune Evasion via Sphingomyelin Metabolism. Gastroenterology.\u00a0(2025). https:\/\/doi.org\/10.1053\/J.GASTRO.2025.03.019.","DOI":"10.1053\/J.GASTRO.2025.03.019"},{"key":"26306_CR36","doi-asserted-by":"crossref","unstructured":"Kasowanjete, P. & Abrahamse, H. Photobiomodulation at 660 nm Stimulates In Vitro Diabetic Wound Healing via the Ras\/MAPK Pathway. Cells. 12, (2023).","DOI":"10.3390\/cells12071080"},{"key":"26306_CR37","doi-asserted-by":"crossref","unstructured":"Banerjee, D. et al. Uncovering the role of tertiary lymphoid organs in the inflammatory landscape: A novel immunophenotype of diabetic foot ulcers. J Cell. Mol. Med 29(7), e70479 (2025).","DOI":"10.1111\/jcmm.70479"},{"key":"26306_CR38","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1038\/s41592-024-02235-4","volume":"21","author":"W Hou","year":"2024","unstructured":"Hou, W. & Ji, Z. Assessing GPT-4 for cell type annotation in single-cell RNA-seq analysis. Nat. Methods. 21, 1462\u20131465 (2024).","journal-title":"Nat. Methods"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-26306-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-26306-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-26306-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T12:44:59Z","timestamp":1764247499000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-26306-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["26306"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-26306-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]},"assertion":[{"value":"19 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"42334"}}