Abstract
Although various malignant tumors have been associated with the aberrant expression of Neural Epidermal Growth Factor-Like 2 (NELL2), its involvement in hepatocellular carcinoma (HCC) has not been previously documented. In this study, NELL2, recognized as a crucial tumor-suppressor gene, was found to be infrequently expressed in HCC. In vitro experiments demonstrated that the overexpression of NELL2 significantly inhibited the proliferation, migration, and invasion of liver cancer cells, whereas the suppression of NELL2 markedly enhanced these oncogenic properties. Further investigation revealed that NELL2 impedes epithelial-mesenchymal transition (EMT) via the Notch signaling pathway. Inhibition of the Notch pathway reversed the increased tumor proliferation, migration, and invasion observed following the downregulation of NELL2 expression. Notably, gene enrichment analysis and in vitro studies indicated that NELL2 effectively induced ferroptosis in HCC cells, as evidenced by increased levels of cellular malondialdehyde (MDA), iron, and Reactive Oxygen Species (ROS), alongside decreased glutathione (GSH) levels. The blockade of the Notch signaling pathway substantially diminished NELL2's capacity to induce ferroptosis. In summary, our findings suggest that NELL2 modulates the Notch signaling pathway to inhibit EMT and promote ferroptosis. Consequently, NELL2 may serve as a novel therapeutic target, potentially functioning as a tumor suppressor gene in HCC.