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

Background and objectives: 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.Materials and methods: 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.Results: 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 upre-gulating transferrin receptor 1 and the HIF-1/IRP1 axis. In NSCLC cells, trabectedin suppresses glutathione peroxidase 4, followed by the Keap1/Nrf2 axis.Conclusions: Our findings imply that trabectedin may treat NSCLC effectively.