Wogonin Suppresses Non-Small Cell Lung Cancer Growth in Association with Oxidative Stress, c-Myc/GPX4 Downregulation and Ferroptosis-Related Responses.

Abstract

<p>Reactive oxygen species (ROS)-regulated antioxidant defense is closely linked to non-small cell lung cancer (NSCLC) progression and therapy resistance. Wogonin (WGN), a flavonoid from Scutellaria baicalensis, has antitumor activity, but whether it is associated with ROS-dependent ferroptotic and mitochondrial stress in NSCLC remains incompletely defined. A549 and BEAS-2B cells, male BALB/c nude mouse A549 xenografts, patient-derived NSCLC organoids, and public transcriptomic cohorts were analyzed using viability, colony formation, migration/invasion, DCFH-DA ROS, JC-1, Annexin V/PI, Fe2+ and lipid ROS probes, RT-qPCR, Western blotting, immunofluorescence, inhibitor rescue, and c-Myc gain- and loss-of-function assays. WGN suppressed A549 growth and motility with weaker effects on BEAS-2B cells. WGN markedly increased intracellular ROS, Fe2+ accumulation and lipid peroxidation, decreased mitochondrial membrane potential, promoted Caspase-related apoptosis, reduced c-Myc/GPX4 and SLC7A11, and increased ACSL4. N-acetylcysteine, Z-VAD-FMK and Ferrostatin-1 partially rescued WGN-induced injury. c-Myc overexpression partially restored GPX4 and reduced lipid ROS/Fe2+ accumulation, whereas c-Myc knockdown decreased GPX4. Xenografts and organoids reproduced tumor inhibition and selected redox-associated molecular changes. Collectively, WGN suppresses A549-associated NSCLC phenotypes in association with ROS accumulation, ferroptosis-related lipid injury, mitochondrial dysfunction-associated apoptosis, and c-Myc/GPX4 downregulation.</p>