Repurposing loratadine to induce ferroptosis and overcome multidrug resistance: preclinical evidence in KB-V-1 cells.

Background: MDR1/P-glycoprotein-mediated multidrug resistance (MDR) limits chemotherapy efficacy across many cancers. Ferroptosis, an iron-dependent regulated cell death driven by lipid peroxidation, offers a potential strategy to bypass MDR. We investigated whether loratadine, an FDA-approved antihistamine, induces ferroptosis and overcomes chemoresistance in MDR1-overexpressing KB-V-1 cells. Methods: Cytotoxicity was evaluated using the CCK-8 assay in multidrug-resistant KB-V-1 cells and chemosensitive KB-3-1 cells. Ferroptosis was verified using specific inhibitors, including ferrostatin-1, liproxstatin-1, and deferoxamine, and compared with the pan-caspase inhibitor Z-VAD-FMK to exclude apoptosis. Hallmarks of ferroptosis (cystine uptake, intracellular glutathione levels, labile iron pool, and lipid peroxidation) were quantitatively assessed. Transcriptomic alterations were analyzed by RNA sequencing (RNA-seq) and further validated by quantitative real-time PCR (qRT-PCR) and Western blot analyses. Results: Loratadine selectively inhibited KB-V-1 viability (IC Conclusion: Loratadine induces ferroptosis in MDR1-overexpressing cells via cystine uptake inhibition, glutathione depletion, and PERK-eIF2α-ATF4 activation, while concurrently downregulating MDR1/P-glycoprotein. These findings support loratadine as a clinically actionable repurposing candidate for ferroptosis-based, resistance-directed cancer therapy.