PLEK2 is upregulated in LUAD and associated with poor prognosis. Knockdown of PLEK2 significantly inhibits LUAD cell proliferation and migration while enhancing apoptosis, and tumor growth in mice injected with PLEK2-silenced cells is impaired. Gene expression profiles and Co-IP analysis show a direct interaction between PLEK2 and SPC25, and downregulation of SPC25 also impairs cell proliferation and migration. Additionally, PI3K/AKT signaling activation is essential for the malignant phenotype induced by PLEK2 in LUAD. Here, AKT1 is linked to neoplasm.