{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:07:43Z","timestamp":1785154063056,"version":"3.55.0"},"reference-count":50,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shanghai Science and Technology Committee Excellent Academic Leaders Program","award":["23XD1405000"],"award-info":[{"award-number":["23XD1405000"]}]},{"name":"Modular Construction Technology and Application of a Field-Mobile Combined Interventional and Surgical Hemostatic Care System for Combat Trauma","award":["BLB23C004"],"award-info":[{"award-number":["BLB23C004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Diabetic foot ulcer (DFU) affects approximately 25% of diabetic patients and represents the leading cause of non-traumatic lower extremity amputation. Neutrophil extracellular traps (NETs) contribute to chronic inflammation; however, their mechanistic role in DFU healing failure remains incompletely characterized. This study integrated bulk RNA sequencing (GSE143735, n = 9) and single-cell RNA sequencing (scRNA-seq; GSE165816, n = 11) datasets to investigate NET-related transcriptional programs. Differential expression analysis identified 96 differentially expressed genes, with significant NET pathway enrichment in non-healers (normalized enrichment score = 4.35, false discovery rate q &lt; 0.001). Analysis of 33,654 single cells revealed elevated NET activity scores in neutrophils from non-healing wounds (p = 4.73 \u00d7 10\u2212159). Four neutrophil subpopulations were identified, with the NETs-high subset expanded in non-healers (43.1% versus 15.4%). Cell\u2013cell communication analysis demonstrated enhanced S100A8\/A9\u2013RAGE and IL1B\u2013IL1R signaling in the non-healing state. A six-gene signature (S100A8, S100A9, MPO, ELANE, NCF1, HMGB1) achieved an area under the receiver operating characteristic curve of 0.750 for healing prediction under leave-one-out cross-validation. These findings implicate NET pathway activation as a potential driver of DFU healing impairment and identify candidate prognostic biomarkers warranting prospective validation.<\/jats:p>","DOI":"10.3390\/ijms27156701","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:54:26Z","timestamp":1785153266000},"page":"6701","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-Omics Profiling Reveals Neutrophil Extracellular Trap Dysregulation in Diabetic Foot Ulcer Healing Impairment"],"prefix":"10.3390","volume":"27","author":[{"given":"Dazhi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Vascular Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shibo","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangxi","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junmin","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0262-7985","authenticated-orcid":false,"given":"Qingsheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1056\/NEJMra1615439","article-title":"Diabetic foot ulcers and their recurrence","volume":"376","author":"Armstrong","year":"2017","journal-title":"N. 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