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Here, we integrated single-cell RNA sequencing (scRNA-seq) of primary tumors and matched metastatic lymph nodes from six GC patients to identify a metastatic epithelial subpopulation characterized by EGR4 overexpression. Kaplan-Meier analysis revealed that high EGR4 expression correlated with reduced survival in GC patients. Mechanistically, chromatin immunoprecipitation sequencing (ChIP-seq) and luciferase assays demonstrated that EGR4 directly bound to the GDF15 promoter, driving its transcriptional activation. Functional studies showed that EGR4 promoted migration and metastasis via GDF15-mediated ErbB3\/ErbB1 hetero-dimerization, which activated PI3K\/AKT and MAPK\/ERK pathways. Furthermore, CellChat analysis identified robust interactions between EGR4\n                    <jats:sup>+<\/jats:sup>\n                    GC cells and cancer-associated fibroblasts (CAFs), particularly extracellular matrix (ECM)-remodeling eCAFs. Secreted GDF15 induced CAF activation through TGF-\u03b2 receptor signaling, creating a pro-metastatic niche. Collectively, our study establishes the EGR4\/GDF15 axis as a critical driver of GC metastasis, offering possible therapeutic targets for intervention.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08095-w","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T13:09:15Z","timestamp":1762520955000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["EGR4 transcriptionally upregulates GDF15 to promote gastric cancer metastasis"],"prefix":"10.1038","volume":"16","author":[{"given":"Weiwei","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisheng","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congcong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihao","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanying","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingling","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"8095_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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