{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T23:38:05Z","timestamp":1769211485010,"version":"3.49.0"},"reference-count":66,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["3UTGM13-175-02S1"],"award-info":[{"award-number":["3UTGM13-175-02S1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P20GM113123"],"award-info":[{"award-number":["P20GM113123"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DaCCoTA CTR"],"award-info":[{"award-number":["DaCCoTA CTR"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U54GM128729"],"award-info":[{"award-number":["U54GM128729"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Gastrointestinal (GI) mucosal injury is a frequent complication of long-term nonsteroidal anti-inflammatory drug (NSAID) use. Effective mucosal healing requires coordinated epithelial migration, proliferation, and angiogenesis, which may be influenced by focal adhesion kinase (FAK). This study aimed to determine whether our newly developed FAK activators promote intestinal mucosal healing by enhancing angiogenesis and whether FAK activation increases resistance to reinjury. Methods: Ischemic jejunal ulcers were induced in C57BL\/6 mice. After 24 h, mice received intraperitoneal injections of the FAK activator ZINC40099027 (ZN27, 900 \u00b5g\/kg every 6 h) or vehicle for 2, 4, or 14 days. Ulcer areas were quantified, and liver and kidney function were assessed. Ulcer and adjacent tissues were analyzed by immunofluorescence staining for angiogenesis and proliferation markers. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with ZN27 to evaluate proliferation, migration, angiogenesis, and intracellular signaling. In a reinjury model, male C57BL\/6J mice received continuous infusion of the FAK activator M64HCl (25 mg\/kg\/day) or vehicle for 7 days, with a single subcutaneous injection of indomethacin (10 mg\/kg) on day 1 to induce GI injury. Fourteen days after the first dose of indomethacin, the mice received a second indomethacin challenge, and one day later, total ulcer areas in the pyloric opening and small intestine were quantified. Results: Ulcer areas were significantly smaller in ZN27-treated mice compared with vehicle-treated controls at 3 and 5 days, accompanied by increased expression of angiogenesis and proliferation markers. In vitro, ZN27 enhanced HUVEC migration via FAK activation in an ERK1\/2-dependent manner and increased the number of angiogenic sprouts. In the reinjury model, treatment with M64HCl during the initial indomethacin-induced injury resulted in significantly smaller ulcer areas in both the pyloric opening and small intestine after the second indomethacin challenge compared with controls. Conclusions: FAK activation accelerates ischemic ulcer healing, in part by enhancing angiogenesis. Moreover, FAK activation during an initial injury reduces susceptibility to recurrent NSAID-induced intestinal injury, perhaps because it promotes initial higher-quality ulcer repair.<\/jats:p>","DOI":"10.3390\/cells15010016","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T11:43:31Z","timestamp":1766403811000},"page":"16","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["FAK-Activated Mucosal Healing Promotes Resistance to Reinjury"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5551-2271","authenticated-orcid":false,"given":"Sema","family":"Oncel","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9292-6198","authenticated-orcid":false,"given":"Guiming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Northeast Ohio Medical University College of Medicine, Rootstown, OH 44272, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4015-2127","authenticated-orcid":false,"given":"Louis","family":"Kwantwi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Northeast Ohio Medical University College of Medicine, Rootstown, OH 44272, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3818-5330","authenticated-orcid":false,"given":"Emilie E.","family":"Vomhof-DeKrey","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA"},{"name":"Department of Surgery, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA"},{"name":"Department of Pathology, University of North Dakota School of Medicine & Health Sciences, Grand Forks, ND 58203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1486-8261","authenticated-orcid":false,"given":"Ricardo","family":"Gallardo-Macias","sequence":"additional","affiliation":[{"name":"Institute for Therapeutics Discovery and Development and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5420-1639","authenticated-orcid":false,"given":"Vadim J.","family":"Gurvich","sequence":"additional","affiliation":[{"name":"Institute for Therapeutics Discovery and Development and Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9696-2789","authenticated-orcid":false,"given":"Marc D.","family":"Basson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Northeast Ohio Medical University College of Medicine, Rootstown, OH 44272, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.7861\/clinmed.2021-0039","article-title":"Non-steroidal anti-inflammatory drugs and the gastrointestinal tract","volume":"21","author":"Tai","year":"2021","journal-title":"Clin. 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