{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:21:40Z","timestamp":1788182500547,"version":"build-2803163510"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"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. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>To investigate the role of NR4A3 in chronic venous ulcer (VU) wound healing and to explore its potential regulatory mechanism involving the PI3K\/Akt pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Differential expression and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the GSE174661 dataset. DEGs were filtered by |log2FC| &amp;gt; 1 and adjusted P &amp;lt; 0.05, with KEGG significance set at P &amp;lt; 0.05. NR4A3 was identified as the core gene. NR4A3 knockdown and overexpression were established in HaCaT cells to evaluate proliferation, migration, and inflammatory cytokines. TNF-\u03b1 was used to mimic the inflammatory microenvironment. Western blotting assessed phosphorylation of GSK3\u03b2, mTOR, PI3K, and Akt. PI3K\/Akt agonist 740Y-P and inhibitor LY294002 were used in rescue experiments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Bioinformatic analysis revealed that NR4A3 expression was markedly downregulated in chronic venous ulcer (VU) tissues relative to normal skin and ordinary acute wound tissues. Differentially expressed genes were significantly enriched in the PI3K\/Akt signaling pathway. TNF-\u03b1 stimulation significantly upregulated NR4A3 expression and increased phosphorylation of GSK3\u03b2 and mTOR in HaCaT cells. In cultured HaCaT keratinocytes, NR4A3 knockdown suppressed cell proliferation and invasion, enhanced cell migration, and elevated the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8, CXCL5), accompanied by reduced phosphorylation of PI3K and Akt. Conversely, NR4A3 overexpression promoted cell proliferation and invasion, restrained migration, and dampened inflammatory responses, while increasing PI3K\/Akt phosphorylation. Treatment with the PI3K\/Akt agonist 740Y-P partially rescued the impaired proliferation, aberrant migration, and excessive inflammation caused by NR4A3 silencing, whereas PI3K\/Akt inhibitor LY294002 aggravated pathway suppression. These findings suggest that NR4A3-associated changes in keratinocyte functions and inflammatory reactions are functionally linked to PI3K\/Akt pathway activity, and inflammatory stimulation activates GSK3\u03b2\/mTOR signaling accompanied by compensatory NR4A3 upregulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that NR4A3 is associated with keratinocyte behavior and inflammatory responses via the PI3K\/Akt pathway, potentially affecting chronic VU progression and healing. Reduced NR4A3 may impair wound repair through inflammation and abnormal cell migration, while TNF-\u03b1 induces compensatory NR4A3 elevation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2026.1822383","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:02:20Z","timestamp":1788181340000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of NR4A3 on wound healing in chronic venous ulcers and its association with the PI3K\/Akt signaling pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Yu","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Intervention Vascular, The Wujin Clinical College of Xuzhou Medical University","place":["Changzhou, Jiangsu, China"]},{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University","place":["Xuzhou, Jiangsu, China"]},{"name":"Department of Interventional Vascular, Wujin People\u2019s Hospital Affiliated with Jiangsu University","place":["Changzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaorong","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Interventional Vascular, Wujin People\u2019s Hospital Affiliated with Jiangsu University","place":["Changzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1186\/ar2605","article-title":"Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration","volume":"11","author":"Andreas","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jscai.2025.103730","article-title":"SCAI technical review on management of chronic venous disease","volume":"4","author":"Attaran","year":"2025","journal-title":"J. Soc Cardiovasc. Angiogr. Interv."},{"key":"B3","doi-asserted-by":"publisher","first-page":"219","DOI":"10.25270\/wnds\/2021.219221","article-title":"Platelet-rich plasma: optimal use in surgical wounds","volume":"33","author":"Bolton","year":"2021","journal-title":"Wounds."},{"key":"B4","first-page":"298","article-title":"Venous ulcers: diagnosis and treatment","volume":"100","author":"Bonkemeyer Millan","year":"2019","journal-title":"Am. Fam. Physician."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1282996","article-title":"ATF5 promotes Malignant T cell survival through the PI3K\/AKT\/mTOR pathway in cutaneous T cell lymphoma","volume":"14","author":"Cao","year":"2023","journal-title":"Front. Immunol."},{"key":"B6","first-page":"231","article-title":"Pharmacological treatment and prevention of chronic venous ulcers: a review","volume":"63","author":"Cerbone","year":"2015","journal-title":"Minerva. Cardioangiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.jdermsci.2023.01.007","article-title":"Investigation of the keratinocyte transcriptome altered in high-glucose environment: an in-vitro model system for precision medicine","volume":"109","author":"Chen","year":"2023","journal-title":"J. Dermatol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.jvsv.2017.03.015","article-title":"Pathophysiology of venous ulceration","volume":"5","author":"Crawford","year":"2017","journal-title":"J. Vasc. Surg. Venous. Lymphat. Disord."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.589770","article-title":"Targeting NR4A nuclear receptors to control stromal cell inflammation, metabolism, angiogenesis, and tumorigenesis","volume":"9","author":"Crean","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2526","DOI":"10.3390\/biomedicines11092526","article-title":"Cellular and molecular processes in wound healing","volume":"11","author":"Fernandez-Guarino","year":"2023","journal-title":"Biomedicines."},{"key":"B11","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1111\/imr.13072","article-title":"NR4A nuclear receptors in T and B lymphocytes: gatekeepers of immune tolerance()","volume":"307","author":"Hiwa","year":"2022","journal-title":"Immunol. Rev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1055\/a-2378-9274","article-title":"Ajuga Taiwanensis extract promotes wound-healing via activation of PDGFR\/MAPK pathway","volume":"90","author":"Hsu","year":"2024","journal-title":"Planta. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s13287-025-04141-8","article-title":"Mesenchymal stem cells from perinatal tissues promote diabetic wound healing via PI3K\/AKT activation","volume":"16","author":"Huang","year":"2025","journal-title":"Stem Cell Res. Ther."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1007\/s11886-024-02140-4","article-title":"Venous insufficiency: wound management","volume":"26","author":"Iceton","year":"2024","journal-title":"Curr. Cardiol. Rep."},{"key":"B15","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1177\/1358863X20947789","article-title":"Role of fibronectin in chronic venous diseases: a review","volume":"25","author":"Kanta","year":"2020","journal-title":"Vasc. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1097\/PRS.0b013e3182362a53","article-title":"Factors associated with poor healing and recurrence of venous ulceration","volume":"129","author":"Labropoulos","year":"2012","journal-title":"Plast. Reconstr. Surg."},{"key":"B17","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1111\/wrr.12102","article-title":"Chronic venous leg ulcer treatment: future research needs","volume":"22","author":"Lazarus","year":"2014","journal-title":"Wound Repair Regen."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2833","DOI":"10.1038\/s41388-022-02303-z","article-title":"Matriptase-2\/NR4A3 axis switches TGF-beta action toward suppression of prostate cancer cell invasion, tumor growth, and metastasis","volume":"41","author":"Lin","year":"2022","journal-title":"Oncogene."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2025.156695","article-title":"Huiyang Shengji decoction promotes healing of diabetic skin ulcers via the NF-kappaB\/STAT3\/NLRP3 signaling pathway: a multi-omics analysis","volume":"143","author":"Lin","year":"2025","journal-title":"Phytomedicine."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2025.115714","article-title":"PFOS promotes lung adenocarcinoma cell proliferation through PI3K\/AKT\/NF-kappaB mediated EMT","volume":"205","author":"Liu","year":"2025","journal-title":"Food Chem. Toxicol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1161\/CIRCRESAHA.123.323699","article-title":"Orphan nuclear receptor NR4A3 promotes vascular calcification via histone lactylation","volume":"134","author":"Ma","year":"2024","journal-title":"Circ. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"11371","DOI":"10.3390\/ijms222111371","article-title":"NR4A3: a key nuclear receptor in vascular biology, cardiovascular remodeling, and beyond","volume":"22","author":"Martinez-Gonzalez","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.xjidi.2021.100018","article-title":"Characterization of human keratinocyte cell lines for barrier studies","volume":"1","author":"Moran","year":"2021","journal-title":"JID. Innov."},{"key":"B24","doi-asserted-by":"publisher","first-page":"24392","DOI":"10.1073\/pnas.2007224117","article-title":"Early programming of CD8(+) T cell response by the orphan nuclear receptor NR4A3","volume":"117","author":"Odagiu","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B25","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.jvsv.2020.04.024","article-title":"Venous ulcers and the need for more appropriate use of venous interventions","volume":"8","author":"Ozsvath","year":"2020","journal-title":"J. Vasc. Surg. Venous. Lymphat. Disord."},{"key":"B26","doi-asserted-by":"publisher","first-page":"29","DOI":"10.3390\/jcm10010029","article-title":"Why venous leg ulcers have difficulty healing: overview on pathophysiology, clinical consequences, and treatment","volume":"10","author":"Raffetto","year":"2020","journal-title":"J. Clin. Med."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70378","article-title":"Immunomodulatory mechanisms of chronic wound healing: translational and clinical relevance","volume":"6","author":"Riaz","year":"2025","journal-title":"MedComm. (2020)."},{"key":"B28","doi-asserted-by":"publisher","first-page":"a041231","DOI":"10.1101\/cshperspect.a041231","article-title":"The role of myofibroblasts in physiological and pathological tissue repair","volume":"15","author":"Schuster","year":"2023","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B29","first-page":"1","article-title":"Cellular and molecular mechanisms of venous leg ulcers development--the \"puzzle\" theory","volume":"29","author":"Simka","year":"2010","journal-title":"Int. Angiol."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202304023","article-title":"Adipose-derived mesenchymal stem cell-derived exosomes biopotentiated extracellular matrix hydrogels accelerate diabetic wound healing and skin regeneration","volume":"10","author":"Song","year":"2023","journal-title":"Adv. Sci. (Weinh)."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2025.106035","article-title":"Effects of culture media on gene expression in reconstructed human epidermis and THP-1 monocytes for skin sensitization evaluation in co-culture systems","volume":"106","author":"Sugimoto-Sawada","year":"2025","journal-title":"Toxicol. Vitro"},{"key":"B32","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.avsg.2024.07.083","article-title":"Clinical guidelines on compression therapy in venous diseases","volume":"110","author":"Sun","year":"2025","journal-title":"Ann. Vasc. Surg."},{"key":"B33","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1186\/s13287-022-02949-2","article-title":"Tideglusib promotes wound healing in aged skin by activating PI3K\/Akt pathway","volume":"13","author":"Sun","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"B34","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1177\/02683555241243167","article-title":"Management of venous leg ulcers","volume":"39","author":"Tan","year":"2024","journal-title":"Phlebology."},{"key":"B35","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1186\/s12951-021-00942-0","article-title":"Hypoxia adipose stem cell-derived exosomes promote high-quality healing of diabetic wound involves activation of PI3K\/Akt pathways","volume":"19","author":"Wang","year":"2021","journal-title":"J. Nanobiotechnol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1007\/s00441-016-2541-4","article-title":"Lung morphometry: the link between structure and function","volume":"367","author":"Weibel","year":"2017","journal-title":"Cell Tissue Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1186\/s13287-020-01755-y","article-title":"Proinflammatory cytokines regulate epidermal stem cells in wound epithelialization","volume":"11","author":"Xiao","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e250068","DOI":"10.1530\/JME-25-0068","article-title":"NR4A3 affects fibrotic activation of orbital fibroblasts and thyroid-associated ophthalmopathy through regulating NF-kappaB signaling","volume":"75","author":"Yi","year":"2025","journal-title":"J. Mol. Endocrinol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2025.119641","article-title":"10-methoxy-leonurine accelerated wound healing through ErbB4\/PI3K-AKT pathway","volume":"346","author":"Zhang","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"10216","DOI":"10.18632\/aging.205920","article-title":"Oxidative stress-induced EGR1 upregulation promotes NR4A3-mediated nucleus pulposus cells apoptosis in intervertebral disc degeneration","volume":"16","author":"Zheng","year":"2024","journal-title":"Aging (Albany. NY)."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2026.1822383\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:02:22Z","timestamp":1788181342000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2026.1822383\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":40,"alternative-id":["10.3389\/fphys.2026.1822383"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2026.1822383","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]},"article-number":"1822383"}}