{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:21:17Z","timestamp":1790108477906,"version":"4.0.1"},"reference-count":33,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2022J011215"],"award-info":[{"award-number":["2022J011215"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2023J011083"],"award-info":[{"award-number":["2023J011083"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2023J011085"],"award-info":[{"award-number":["2023J011085"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Dermatology"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Previous studies have unequivocally established the efficacy of gefitinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR\u2010TKIs), in the management of patients afflicted with advanced Non\u2010Small Cell Lung Cancer (NSCLC). Nonetheless, the manifestation of cutaneous toxicities of varying severity has been observed to compromise patient survival outcomes and limit its clinical applicability. Elucidating the mechanistic underpinnings of gefitinib\u2010induced dermal barrier dysfunction is imperative, as it holds the potential to inform future therapeutic strategies and facilitate the development of innovative pharmacological interventions. Utilising a multi\u2010modal approach, this study employed network pharmacology and molecular docking techniques to identify potential etiological factors of gefitinib\u2010induced dermal barrier dysfunction. Oral administration of gefitinib was conducted to establish a clinical model, followed by Haematoxylin and Eosin (HE) staining for epidermal and stratum corneum morphological assessment, and immunohistochemical quantification of Keratins 1 (K1) and K10 and Desmoglein\u20101 (DSG\u20101). Molecular expression levels of K10, K17, Claudin\u20104 (CLDN4), Interleukin\u20106 (IL\u20106), Tumour Necrosis Factor\u2010\u03b1 (TNF\u2010\u03b1), and Ephrin Type\u2010A Receptor 2 (EPHA2) were evaluated in HaCaT keratinocytes using Reverse Transcription Quantitative Polymerase Chain Reaction (RT\u2010qPCR) and Western Blot assays. Additionally, EPHA2 mRNA and protein expression in murine cutaneous tissues were ascertained through RT\u2010qPCR and Western Blot analyses. Network pharmacology and molecular docking implicated EPHA2 as a central mediator in gefitinib\u2010induced epidermal barrier dysfunction pathways. In murine models, gefitinib administration resulted in palpebral desquamation and dorsal cutaneous erythema, accompanied by elevated expression of K1, K17, and DSG\u20101 and epidermal hyperplasia. Furthermore, gefitinib augmented K10, K17, IL\u20106, and TNF\u2010\u03b1 expression in HaCaT cells, significantly attenuated cellular viability, and suppressed CLDN4 expression. EPHA2 mRNA and protein expression were notably downregulated in both HaCaT cells and BALB\/c murine models. Ephrin\u2010A1 Fc, an EPHA2 agonist, effectively mitigated gefitinib\u2010induced cutaneous damage and inflammation, while concurrently downregulating K10, K17, IL\u20106, and TNF\u2010\u03b1 expression in HaCaT cells and upregulating CLDN4 expression. Gefitinib appears to induce dermal barrier dysfunction via the downregulation of EPHA2 expression.<\/jats:p>","DOI":"10.1111\/exd.70145","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T05:55:38Z","timestamp":1753854938000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mechanism Study on Inhibition of <scp>EPHA2<\/scp> Expression Impaired Skin Barrier Function by Gefitinib"],"prefix":"10.1111","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1636-9864","authenticated-orcid":false,"given":"Jiang\u2010Yuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Ningde Municipal Hospital of Ningde Normal University  Ningde Fujian China"},{"name":"Shanghai General Hospital Ningde Hospital  Ningde Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010Kun","family":"Nie","sequence":"additional","affiliation":[{"name":"Ningde Municipal Hospital of Ningde Normal University  Ningde Fujian China"},{"name":"Shanghai General Hospital Ningde Hospital  Ningde Fujian China"},{"name":"Innovation Team of Clinical Pharmacy Service (2023T06) Ningde Normal University  Ningde Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi\u2010Chun","family":"Chen","sequence":"additional","affiliation":[{"name":"Ningde Municipal Hospital of Ningde Normal University  Ningde Fujian China"},{"name":"Shanghai General Hospital Ningde Hospital  Ningde Fujian China"},{"name":"Innovation Team of Clinical Pharmacy Service (2023T06) Ningde Normal University  Ningde Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su\u2010Juan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Ningde Municipal Hospital of Ningde Normal University  Ningde Fujian China"},{"name":"Shanghai General Hospital Ningde Hospital  Ningde Fujian 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