Ferroptosis is crucial for tumor growth inhibition. Moreover, ferroptosis has been considered as a potential strategy against cancer. The present study focused on the mechanism of ferroptosis induction by β-elemene during the lung cancer (extracted from the Chinese medicine Curcuma Wen yujin). CCK-8 assay, flow cytometry and biochemical assays including intracellular ROS, MDA, GSH, iron and 8-OHdG level were performed. DNA polymerase epsilon subunit 2 (Pole2) and the ferroptosis-related proteins were studied by utilizing western blotting. The study results showed that the β-elemene reduced the viability of lung cancer cells via ferroptosis. Furthermore, multiple experiments confirmed that Pole2 knockdown enhanced the production of lipid ROS, MDA and iron, leading to the iron-dependent ferroptosis in lung cancer cells. Overexpression of Pole2 inhibited β-elemene-induced ferroptosis through reduction of iron-dependent oxidative damage. Mechanically, Pole2 reduced the upregulation of p53 expression, and increased the phosphorylation levels of PI3K and AKT in β-elemene-induced cells. Overexpression of TP53 or the inhibitor of PI3K/AKT pathway reversed the effects of Pole2. Together, β-elemene evoked ferroptosis through the Pole2-regulated p53 or PI3K/AKT signalling, and might be an effective therapy for lung carcinogenesis.Copyright © 2022 Elsevier B.V. All rights reserved.