Neodymium Nitrate Suppresses Malignant Phenotypes in Hep-G2 Cells by Targeting Nrf2 to Inhibit EMT and Induce Ferroptosis.

Hepatocellular carcinoma (HCC) is characterized by a poor prognosis, largely driven by metastasis and therapy resistance, processes closely linked to epithelial-mesenchymal transition (EMT) and ferroptosis. Neodymium nitrate (Nd(NO3)3), a predominant neodymium species, has shown antitumor potential, yet its specific effects and underlying mechanisms in HCC remain poorly understood. This study investigated whether Nd(NO3)3 exerts anti-malignant effects in Hep-G2 cells through the Nrf2-ferroptosis axis. We treated Hep-G2 cells with Nd(NO3)3 and assessed proliferation (CCK-8), migration, invasion (wound-healing and Transwell assays), EMT markers (E-cadherin, Vimentin), Nrf2 and GPx4 expression (Western blotting, qRT-PCR), and ferroptosis indicators (ROS, MDA, GSH, Fe2+/Fe3+). Low-dose Nd(NO3)3 significantly inhibited migration, invasion, and EMT-associated marker expression without affecting proliferation and promoted ferroptotic phenotypes, as evidenced by elevated ROS, MDA, and ferrous iron expression; decreased GSH levels; and downregulated GPx4 expression. Mechanistically, Nd(NO3)3 downregulated Nrf2 expression. Nrf2 overexpression reversed the suppression of migration, invasion, EMT-associated markers, and ferroptotic phenotypes, while the ferroptosis inhibitor deferoxamine rescued migration and invasion. These findings suggest that Nd(NO3)3 exerts anti-malignant effects in Hep-G2 cells by targeting Nrf2 to coordinately suppress EMT and promote ferroptosis, identifying the Nrf2-ferroptosis axis as a potential therapeutic target in HCC cells. However, these findings are based on in vitro experiments in a single Hep-G2 cell line with n = 3 biological replicates, which limits statistical power and generalizability; the results should therefore be interpreted as preliminary evidence requiring further validation in additional cell lines and in vivo models.