{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:17:43Z","timestamp":1785421063501,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2025-18362970"],"award-info":[{"award-number":["RS-2025-18362970"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2018-NR031048"],"award-info":[{"award-number":["RS-2018-NR031048"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2025-18362970"],"award-info":[{"award-number":["RS-2025-18362970"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RS-2018-NR031048"],"award-info":[{"award-number":["RS-2018-NR031048"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Ministry of Health & Welfare","doi-asserted-by":"publisher","award":["RS-2025-25459824"],"award-info":[{"award-number":["RS-2025-25459824"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Ministry of Health & Welfare","doi-asserted-by":"publisher","award":["RS-2025-25456722"],"award-info":[{"award-number":["RS-2025-25456722"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2025-25459824"],"award-info":[{"award-number":["RS-2025-25459824"]}],"id":[{"id":"https:\/\/ror.org\/00vxgjw72","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RS-2025-25456722"],"award-info":[{"award-number":["RS-2025-25456722"]}],"id":[{"id":"https:\/\/ror.org\/00vxgjw72","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"Ministry of Education","doi-asserted-by":"publisher","award":["RS-2024-00442483"],"award-info":[{"award-number":["RS-2024-00442483"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2024-00442483"],"award-info":[{"award-number":["RS-2024-00442483"]}],"id":[{"id":"https:\/\/ror.org\/01p262204","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Protease-activated receptor 1 (PAR1), a G protein-coupled receptor, plays a central role in coordinating multiple phases of cutaneous wound healing, including hemostasis, cell proliferation, migration, and extracellular matrix remodeling. Despite its therapeutic potential, PAR1-selective positive allosteric modulators (PAMs) remain limited. Here, we characterized the wound healing efficacy of gestodene, a third-generation progestin previously identified as a selective PAM of PAR1. Gestodene exhibited no intrinsic agonist activity but selectively potentiated PAR1-activating peptide (PAR1-AP)-induced calcium signaling without affecting PAR2 or PAR4 responses. Consistently, gestodene induced a concentration-dependent leftward shift in the PAR1-AP dose\u2013response curve. Notably, gestodene enhanced PAR1-dependent cell proliferation, migration, and ERK1\/2 activation, effects abolished by PAR1 knockout or pharmacological inhibition with vorapaxar in human keratinocytes (HaCaT) and dermal fibroblasts (HDF). Gestodene also potentiated the expression of wound healing-associated genes, including matrix metalloproteinases (MMP-1, -2, -3, -10), fibronectin, and type I collagen (COL1A1). In a murine wound model, topical administration of gestodene accelerated wound closure, achieving complete re-epithelialization by Day 8 and significantly enhancing collagen deposition, effects reversed by vorapaxar. Collectively, these findings demonstrate that gestodene accelerates cutaneous wound healing through PAR1-selective positive allosteric modulation and supports its potential as a drug repositioning candidate for wound repair.<\/jats:p>","DOI":"10.3390\/ijms27125502","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T07:33:54Z","timestamp":1781768034000},"page":"5502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gestodene Accelerates Cutaneous Wound Healing via PAR1-Selective Positive Allosteric Modulation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0711-0766","authenticated-orcid":false,"given":"Hyejin","family":"Jeon","sequence":"first","affiliation":[{"name":"College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3780-7695","authenticated-orcid":false,"given":"Yunkyung","family":"Heo","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3224-6510","authenticated-orcid":false,"given":"Yechan","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0414-6245","authenticated-orcid":false,"given":"So-Hyeon","family":"Park","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mincheol","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1480-7433","authenticated-orcid":false,"given":"Wan","family":"Namkung","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea"},{"name":"Woo Choo Lee Institute for Precision Drug Development, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1e-S\u201332e-S","DOI":"10.1097\/01.prs.0000225428.38108.67","article-title":"Wound healing: An overview","volume":"117","author":"Janis","year":"2006","journal-title":"Plast. 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