{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:30:48Z","timestamp":1786595448526,"version":"build-2736575974"},"reference-count":83,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Diabetic foot ulcer (DFU) is a heterogeneous chronic wound in which the orderly sequence of inflammation, repair, and remodeling is replaced by persistent non-healing. Although bulk transcriptomic profiling and histopathology have revealed inflammatory imbalance and protease dysregulation, they cannot resolve the cell states, intercellular communication, and spatial niches that sustain chronicity or define residual reparative capacity. Recent single-cell and spatial studies are redefining DFU as a dynamic cellular ecosystem comprising epithelial, stromal, immune, vascular, and adnexal populations with distinct states and transitions. This review synthesizes these emerging datasets and proposes a mechanistic framework in which DFU chronicity is driven by four interrelated domains: epidermal arrest, characterized by stress-adapted basal keratinocytes that fail to complete activation-to-differentiation programs; immune-stromal lock-in, maintained by chemokine-mediated leukocyte recruitment, protease-biased matrix turnover, and defective resolution of inflammation; vascular dysfunction with neurovascular uncoupling, marked by endothelial stress, impaired angiogenesis, hypoperfusion, hypoxia, and loss of neurovascular and eccrine-associated homeostatic support; and proliferative arrest with senescence burden, in which persistent p21-associated cell-cycle arrest and senescent cell accumulation limit regenerative capacity while amplifying inflammatory and proteolytic signaling. Together, these cellular and spatial features provide a unifying explanation for DFU non-healing and highlight candidate biomarkers, therapeutic opportunities, and translational priorities required to convert descriptive atlases into actionable interventions.<\/jats:p>","DOI":"10.3389\/fmed.2026.1910324","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:24:47Z","timestamp":1786595087000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell mapping of diabetic foot ulcers: mechanistic axes and therapeutic targets"],"prefix":"10.3389","volume":"13","author":[{"given":"Haoyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Burns, Beijing Jishuitan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjia","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Burns, Beijing Jishuitan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengkai","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Burns, Beijing Jishuitan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmedur Rahman","family":"Sabuj","sequence":"additional","affiliation":[{"name":"National Institute of Burn and Plastic Surgery","place":["Dhaka, Bangladesh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mridul Kanti","family":"Sarker","sequence":"additional","affiliation":[{"name":"National Institute of Burn and Plastic Surgery","place":["Dhaka, Bangladesh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Burns, Beijing Jishuitan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Peking University Fourth School of Clinical Medicine","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1056\/NEJMra1615439","article-title":"Diabetic foot ulcers and their recurrence","volume":"376","author":"Armstrong","year":"2017","journal-title":"N Engl J Med"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"209","DOI":"10.2337\/dci22-0043","article-title":"Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers","volume":"46","author":"McDermott","year":"2023","journal-title":"Diabetes 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