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The non-receptor tyrosine kinase Fyn, recognized for its role in regulating tumor cell survival and drug resistance, has emerged as a promising therapeutic target in melanoma treatment. In this study, we conducted a virtual screening and identified TAE684 as a potent inhibitor of Fyn. Utilizing in vitro assays, including assessments of cell viability, reactive oxygen species (ROS) production and DNA damage, alongside an in vivo melanoma xenograft model, we demonstrated that either TAE684 treatment or Fyn knockdown resulted in increased ROS levels and DNA damage, ultimately inducing cell cycle arrest at the G2\/M phase and apoptosis in melanoma cells. Significantly, the application of TAE684 in melanoma cells demonstrated a capacity to counteract vemurafenib resistance, presumably through the down-regulation of the AP-1 pathway. Furthermore, the combination of TAE684 with vemurafenib exhibits a synergistic effect, leading to decreased cell viability in melanoma cells resistant to vemurafenib treatment. These results highlight the potential of TAE684 as a dual-function agent that not only inhibits melanoma proliferation but also reverses resistance to vemurafenib by targeting Fyn, thereby establishing it as a promising candidate for melanoma therapy.<\/jats:p>","DOI":"10.1038\/s41419-025-08090-1","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T15:23:48Z","timestamp":1762442628000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fyn inhibition by TAE684: A synergistic strategy to suppress melanoma and reverse vemurafenib resistance"],"prefix":"10.1038","volume":"16","author":[{"given":"Waner","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeye","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7104-5490","authenticated-orcid":false,"given":"Cong","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8187-636X","authenticated-orcid":false,"given":"Xiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"8090_CR1","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1001\/jamadermatol.2022.0160","volume":"158","author":"M Arnold","year":"2022","unstructured":"Arnold M, Singh D, Laversanne M, Vignat J, Vaccarella S, Meheus F, et al. 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