Erastin-Induced Ferroptosis Overcomes Oxaliplatin Resistance in Colorectal Cancer Cells

Chemotherapy resistance remains a significant obstacle in the treatment of colorectal cancer (CRC) patients. Here, we examined the ferroptosis susceptibility of the chemotherapy-resistant CRC cell line HCT116-OxR relative to its parental counterpart. The increased basal levels of reactive oxygen species (ROS) and ferroptosis-associated proteins observed in HCT116-OxR cells rendered them more sensitive to erastin-induced cell death, as determined by the MTT and soft agar assays. Mechanistically, erastin elicited a reduction in mitochondrial membrane potential (MMP). Notably, this loss of MMP was not accompanied by detectable apoptotic changes, suggesting that a non-apoptotic cell death pathway may be involved. Rather, erastin elevated intracellular iron and ROS concentrations, resulting in lipid peroxidation consistent with ferroptosis. The pivotal involvement of ROS was supported by N-Acetyl-L-cysteine pretreatment, and ferrostatin-1 pretreatment further verified that erastin-induced cell death was mediated by ferroptosis. The heightened erastin sensitivity of HCT116-OxR cells suggests a therapeutic vulnerability that could be exploited to induce ferroptosis in chemotherapy-resistant CRC. This ferroptosis susceptibility may offer a promising strategy for overcoming treatment resistance and improving therapeutic outcomes.