{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:32:42Z","timestamp":1753878762247,"version":"3.41.2"},"reference-count":58,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Neuronal PAS domain protein 2 (NPAS2) is critical in tissue fibrosis. Hypertrophic scars (HTS), a form of skin fibrosis, are characterised by excessive myofibroblast proliferation and abnormal extracellular matrix (ECM) deposition. However, whether NPAS2 contributes to skin fibrosis and the development of HTS remains unclear. In this study, the expression of NPAS2 between normal skin and hypertrophic scars (HTS) was assessed using RT\u2010qPCR and immunohistochemistry (IHC). Human dermal fibroblasts (HDFs) and HTS\u2010derived fibroblasts (HTS\u2010Fs) were isolated from normal skin and HTS, respectively. NPAS2 was knocked down in HTS\u2010Fs and overexpressed in HDFs via gene transfection. Cell proliferation and migration of transfected HTS\u2010Fs and HDFs were analysed using flow cytometry, CCK\u20108 and transwell assays. The expressions of NPAS2, CLOCK, BMAL1, COL I, COL III, \u03b1\u2010SMA and CDC25A were evaluated by western blotting and RT\u2010qPCR. Dual\u2010luciferase reporter assays and chromatin immunoprecipitation (ChIP) identified the regulatory effect of NPAS2 on CDC25A. In\u00a0vivo, an 8 \u00d7\u20098\u2009mm full\u2010thickness skin defect was created on the tail of SD rats, with viral particles (1 \u00d7\u2009107) of r\u2010plenR\u2010sh\u2010NPAS2 or r\u2010plenR\u2010NPAS2\u2010NC injected subcutaneously at the wound edges weekly. Tissue samples, histopathological analyses and photographs were taken until the wound healed completely. The results indicated that NPAS2 was significantly upregulated in HTS. The proliferation, migration, and expression of COL I, COL III, and \u03b1\u2010SMA were higher in HDFs overexpressing NPAS2 than those of HDFs themselves. In contrast, the behaviours mentioned above of HTS\u2010Fs knocking down NPAS2 were lower than that of HTS\u2010Fs. Mechanistically, the migration and proliferation promoting effect of NPAS2 was mediated by the binding of NPAS2 to the E\u2010like\u2010box of CDC25A. In\u00a0vivo, compared with the r\u2010plenR\u2010NPAS2\u2010NC group, the re\u2010epithelialised regions of r\u2010plenR\u2010sh\u2010NPAS2 were pink, flat and as large as the initial wound. In addition, their dermal structures were similar to skin and possessed loose and regular collagen arrangement which was parallel to the epidermis. Take together, these findings suggested that compared with HDFs, NPAS2 was upregulated in HTS\u2010Fs. NPAS2 promoted the activation of HDFs, which is characterised by stronger proliferation and migration and the higher level of \u03b1\u2010SMA, COL I and COL III. In which, the proliferation and migration effects of NPAS2 were mediated by CDC25A. Furthermore, NPAS2 knocked down in rat tail wounds inhibited the HTS formation. Therefore, NPAS2 may serve as a potential therapeutic target for HTS in the future.<\/jats:p>","DOI":"10.1111\/jcmm.70643","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T13:34:35Z","timestamp":1750685675000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Circadian Gene <scp>NPAS2<\/scp> Relieves Hypertrophic Scar Formation via <scp>CDC25A<\/scp>\u2010Mediated Fibroblasts Activity"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5373-5766","authenticated-orcid":false,"given":"Pei","family":"Wei","sequence":"first","affiliation":[{"name":"Burn &amp; Wound Repair Department Fujian Medical University Union Hospital  Fuzhou Fujian China"},{"name":"Fujian Burn Institute Fujian Medical University Union Hospital  Fuzhou Fujian China"},{"name":"Fujian Burn Medical Center Fujian Medical University Union Hospital  Fuzhou Fujian China"},{"name":"Fujian Provincial Key Laboratory of Burn and Trauma Fujian Medical University Union Hospital  Fuzhou Fujian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongqiang","family":"Xiao","sequence":"additional","affiliation":[{"name":"Plastic Surgery Department of Shanghai Ninth People's Hospital Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaorong","family":"Xu","sequence":"additional","affiliation":[{"name":"Burn &amp; 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