Lapatinib suppresses cysteine deprivation-induced ferroptotic cell death by modulating mitochondrial function

Abstract

Ferroptosis, an iron-dependent regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for cancer. Although lapatinib has been reported to induce ferroptosis in several cancer types, we found that it exerts a ferroptosis-suppressive effect under cysteine deprivation. Lapatinib alone induced a mild ferroptotic phenotype (< 10% cell death), accompanied by increased intracellular reactive oxygen species (ROS) generation, lipid peroxidation, and intracellular labile iron (Fe²⁺) accumulation. In contrast, under cysteine deprivation, lapatinib markedly attenuated ferroptotic cell death by suppressing intracellular ROS generation and lipid peroxidation without reducing intracellular Fe²⁺ accumulation. Lapatinib attenuated cysteine deprivation-induced ferroptosis despite further reductions of glutathione (GSH) levels and glutathione peroxidase 4 (GPX4) expression. Moreover, lapatinib also suppressed ferroptosis induced by the direct GPX4 inhibitor RSL3. Lapatinib attenuated cysteine deprivation-induced mitochondrial responses, as evidenced by reduced mitochondrial membrane potential hyperpolarization and oxygen consumption. Collectively, these results demonstrate that lapatinib exerts context-dependent effects, suppressing cysteine deprivation- induced ferroptosis despite inducing a mild ferroptotic phenotype when used alone. Lapatinib suppresses cysteine deprivation-induced ferroptosis. Lapatinib suppresses ferroptosis despite reduced GSH levels and GPX4 expression. Lapatinib attenuates cysteine deprivation-induced mitochondrial metabolic activation.