Trabectedin induces ferroptosis via regulation of HIF-1α/IRP1/TFR1 and Keap1/Nrf2/GPX4 axis in non-small cell lung cancer cells

Non-small cell lung cancer (NSCLC) is a global health concern. NSCLC treatment outcomes are generally poor due to treatment resistance or toxicity. Ferroptosis is a novel cell death triggered by iron accumulation, reactive oxygen species (ROS), and lipid peroxidation. Ferroptosis may kill cancer cells, particularly those resistant to apoptosis. The Cell Counting Kit-8 assay assessed NSCLC cell viability after trabectedin treatment. Flow cytometry with Annexin V-FITC staining evaluated cell death. ROS, iron, lipid peroxidation, and GSH levels were measured using commercial kits. qRT-PCR and western blots evaluated messenger RNA and protein levels. Proteins were inhibited using short interfering RNA transfection and specific inhibitors. Trabectedin was cytotoxic to NSCLC cells regardless of p53 status. Trabectedin upregulated iron, ROS, and lipid peroxidation in NSCLC cells, causing ferroptosis. Trabectedin increases iron and ROS levels by upregulating transferrin receptor 1 and the HIF-1/IRP1 axis. In NSCLC cells, trabectedin suppresses glutathione peroxidase 4, followed by the Keap1/Nrf2 axis. Our findings imply that trabectedin may treat NSCLC effectively.