In this study, we found that (1) GBM patients with lower LCN2 expression and higher CTSD expression had a poorer prognosis; (2) LCN2 expression inhibited the cytotoxic effects in GBM cells; (3) overexpression of LCN2 inhibited the invasion and migration of malignant GBM cells in vitro; (4) overexpression of LCN2 exerted anti-metastatic effects by suppressing CTSD expression via upregulation of the ERK signaling pathway. The gene discussed is CTSD; the disease is glioblastoma.