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Studies have shown that IGF2BP3, an oncofetal protein and an m6A reader, overexpresses and correlates to lymph node metastasis and worse overall survival in histopathological studies including NSCLC, but its mechanism needs further study. This study explored IGF2BP3's function and mechanism in LUAD lymphatic metastasis using public databases, a human LUAD tissue microarray, human LUAD cells, and a lymphatic metastasis model in male BALB\/c nude mice. Firstly, we proved that IGF2BP3 overexpression was positively correlated to patients' lymph node metastasis and worse overall survival in bioinformatics and a human LUAD tissue microarray analysis. IGF2BP3 was knocked out or overexpressed in human LUAD cell lines. Functionally, IGF2BP3 facilitated NCI\u2010H1299, NCI\u2010H358, and A549 cell growth, migration, invasion, and EMT in\u00a0vitro, and promoted tumorigenesis, lymphangiogenesis, and lymphatic metastasis of NCI\u2010H1299 cells in BALB\/c nude mice. Mechanically, RIP, RNA pull\u2010down assay, MeRIP, mRNA stability assays, rescue experiments, and immunohistochemical assays were conducted. IGF2BP3 was demonstrated to bind to the m6A site of the 3\u2032UTR region of SRC, stabilizing its mRNA and activating the downstream STAT3 signaling pathway and lymphatic growth factors such as VEGF\u2010C, therefore affecting lymphatic metastasis. The cell migration and EMT function of IGF2BP3 were partially rescued by utilizing SRC siRNA or AZD0530, an SRC inhibitor. This study demonstrated that IGF2BP3 promotes lymphatic metastasis in LUAD via activating the m6A\u2010SRC\u2010STAT3\u2010VEGFC signaling axis, indicating that IGF2BP3 is a potential therapeutic target to overcome metastasis in LUAD patients.<\/jats:p>","DOI":"10.1111\/cas.16451","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T02:25:31Z","timestamp":1736821531000},"page":"936-950","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["IGF2BP3 Triggers STAT3 Pathway by Stabilizing SRC RNA in an <scp>m6A<\/scp>\u2010Dependent Manner to Promote Lymphatic Metastasis in LUAD"],"prefix":"10.1111","volume":"116","author":[{"given":"Jiapei","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Radiotherapy &amp; Oncology The Second Affiliated Hospital of Soochow University  Suzhou Jiangsu China"},{"name":"Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology 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