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N6-methyladenosine (m<jats:sup>6<\/jats:sup>A) stands as one of the most abundant modifications on the mRNA transcriptome. However, in the metastasis of gallbladder carcinoma (GBC), the effect of TGF-\u03b21 with mRNA m<jats:sup>6<\/jats:sup>A modification, especially the effect of mRNA translation efficiency associated with m<jats:sup>6<\/jats:sup>A modification, remains poorly elucidated. Here we demonstrated a negative correlation between FOXA1 and TGF-\u03b21 expression in GBC. Overexpression of FOXA1 inhibited TGF-\u03b21-induced migration and epithelial-mesenchymal transition (EMT) in GBC cells. Mechanistically, we confirmed that TGF-\u03b21 suppressed the translation efficiency of FOXA1 mRNA through polysome profiling analysis. Importantly, both in vivo and in vitro experiments showed that TGF-\u03b21 promoted m<jats:sup>6<\/jats:sup>A modification on the coding sequence (CDS) region of FOXA1 mRNA, which was responsible for the inhibition of FOXA1 mRNA translation by TGF-\u03b21. We demonstrated through MeRIP and RIP assays, dual-luciferase reporter assays and site-directed mutagenesis that ALKBH5 promoted FOXA1 protein expression by inhibiting m<jats:sup>6<\/jats:sup>A modification on the CDS region of FOXA1 mRNA. Moreover, TGF-\u03b21 inhibited the binding capacity of ALKBH5 to the FOXA1 CDS region. Lastly, our study confirmed that overexpression of FOXA1 suppressed lung metastasis and EMT in a nude mice lung metastasis model. In summary, our research findings underscore the role of TGF-\u03b21 in regulating TGF-\u03b21\/FOXA1-induced GBC EMT and metastasis by inhibiting FOXA1 translation efficiency through m<jats:sup>6<\/jats:sup>A modification.<\/jats:p>","DOI":"10.1038\/s41419-024-06800-9","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T15:02:25Z","timestamp":1718636545000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["TGF-\u03b21 facilitates gallbladder carcinoma metastasis by regulating FOXA1 translation efficiency through m6A modification"],"prefix":"10.1038","volume":"15","author":[{"given":"Zhenheng","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiming","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijie","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiahenazi","family":"Abudukeremu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"She","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4407-4880","authenticated-orcid":false,"given":"Yanling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,17]]},"reference":[{"key":"6800_CR1","doi-asserted-by":"publisher","first-page":"106234","DOI":"10.1016\/j.ijsu.2022.106234","volume":"98","author":"CF Feo","year":"2022","unstructured":"Feo CF, Ginesu GC, Fancellu A, Perra T, Ninniri C, Deiana G, et al. 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