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In hepatocellular carcinoma (HCC) cells, EphA2 is proteolytically cleaved by membrane-type 1 matrix metalloproteinase (MT1-MMP), producing a C-terminal fragment (EphA2-CF) and an N-terminal fragment (EphA2-NF). The functional role of these cleavage fragments on HCC remains unclear. Herein, we investigated their roles in hepatocarcinogenesis and malignant progression. Western blotting and membrane biotinylation assays revealed that EphA2-CF was present in HCC cells co-expressing EphA2 and MT1-MMP. EphA2-CF-expressing cells were resistant to EA1-induced growth suppression, while MT1-MMP knockdown restored EA1 sensitivity. In Hep3B cells, stable EphA2-CF expression confirmed resistance to EA1-mediated inhibition of proliferation and survival. Mechanistically, EphA2-CF sustained oncogenic signaling through constitutive phosphorylation at EphA2-S\n                    <jats:sup>897<\/jats:sup>\n                    , while failing to induce Y\n                    <jats:sup>588<\/jats:sup>\n                    phosphorylation after EA1 stimulation. Mutation of EphA2-S\n                    <jats:sup>897<\/jats:sup>\n                    abolished EphA2-CF-driven proliferation and survival. Reverse-phase protein array identified activation of the EGFR-AKT axis and inactivation of GSK3\u03b2 as key downstream events. Both pharmacological inhibition of EGFR or AKT, and activation of GSK3\u03b2 suppressed EphA2-CF-driven proliferation. Furthermore, enforced expression of a constitutively active GSK3\u03b2 mutant (S9A) markedly suppressed EphA2-CF\u2013driven tumorigenesis in mice, genetically validating GSK3\u03b2 inactivation as a critical effector of EphA2-CF oncogenic signaling. In addition, soluble EphA2-NF functioned as a decoy receptor for EA1, blocking its tumor-suppressive activity. These findings demonstrate that MT1-MMP\u2013mediated EphA2 processing promotes HCC malignancy via dual mechanisms: EphA2-CF drives ligand-independent EGFR\/AKT\/GSK3\u03b2 signaling, while EphA2-NF inhibits EA1-mediated tumor suppression.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-09024-1","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T02:56:03Z","timestamp":1782701763000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteolytic EphA2 fragments cooperatively promote hepatocellular carcinoma progression"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0407-0420","authenticated-orcid":false,"given":"Kazuki","family":"Ikeda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiko","family":"Asakura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soyogi","family":"Sengoku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiki","family":"Tsukamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuaki","family":"Funahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4539-888X","authenticated-orcid":false,"given":"Naohiko","family":"Koshikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"9024_CR1","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1038\/nrc2806","volume":"10","author":"EB Pasquale","year":"2010","unstructured":"Pasquale EB. 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All experiments involving recombinant DNA were approved by the Institutional Biosafety Committee of the Institute of Science Tokyo (Approval No. I2025019) and conducted in compliance with the institutional regulations and applicable guidelines governing recombinant DNA research. The analyses of human tumor protein expression RPPA data were performed using publicly available datasets obtained from The Cancer Proteome Atlas (TCPA). These datasets contain de-identified information and are exempt from additional institutional ethical review and informed consent requirements.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All authors have read and approved the final version of the manuscript and consent to its publication in Cell Death & Disease.","order":3,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"799"}}