Objective: To investigate the effect of xanthohumol (XN) on the proliferation inhibition and death mode of SK-N-SH human neuroblastoma cells and to explore the death mechanism of SK-N-SH cells from the perspective of redox homeostasis. Methods: Cell viability was observed by the sulforhodamine B (SRB) assay to determine appropriate concentrations of XN for subsequent experiments. Flow cytometry was used to detect lipid reactive oxygen species (ROS) levels. The effect of XN on intracellular Fe2+ levels was observed by fluorescence microscopy. The effect of XN on the protein expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) was detected by Western blot analysis. Results: XN inhibited the proliferation of SK-N-SH cells and induced cell death. After XN treatment, the level of lipid peroxidation significantly increased, the levels of glucose-6-phosphate dehydrogenase (G6PDH), reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) remarkably decreased, Fe2+ overload occurred, and the expression of GPX4 and FTH1 decreased. Ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, reversed cell proliferation inhibition and damage induced by XN and significantly attenuated XN-induced oxidative stress and Fe2+ overload. Conclusion: XN induces ferroptosis in SK-N-SH cells by inducing redox imbalance and Fe2+ overload
