<p>EphA2 is a receptor tyrosine kinase that suppresses tumor growth when bound by its ligand ephrin-A1 (EA1), but promotes tumor progression in the absence of ligand. 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-S⁸⁹⁷, while failing to induce Y⁵⁸⁸ phosphorylation after EA1 stimulation. Mutation of EphA2-S⁸⁹⁷ abolished EphA2-CF-driven proliferation and survival. Reverse-phase protein array identified activation of the EGFR-AKT axis and inactivation of GSK3β as key downstream events. Both pharmacological inhibition of EGFR or AKT, and activation of GSK3β suppressed EphA2-CF-driven proliferation. Furthermore, enforced expression of a constitutively active GSK3β mutant (S9A) markedly suppressed EphA2-CF–driven tumorigenesis in mice, genetically validating GSK3β 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–mediated EphA2 processing promotes HCC malignancy via dual mechanisms: EphA2-CF drives ligand-independent EGFR/AKT/GSK3β signaling, while EphA2-NF inhibits EA1-mediated tumor suppression.</p>