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. In vivo antitumor efficacy was examined in a KB-V-1 xenograft model following treatment with loratadine (20 mg/kg, intraperitoneal), paclitaxel, or their combination. Results Loratadine selectively inhibited KB-V-1 viability (IC 50 = 2.0 µM) while sparing KB-3–1 cells (IC 50 =48.45 µM). Cell death was effectively rescued by ferroptosis inhibitors, confirming ferroptosis as the primary mechanism. Loratadine suppressed cystine uptake, depleted glutathione, elevated labile iron, and promoted lipid peroxidation comparably to erastin. RNA-seq identified 1,861 differentially expressed genes enriched in the PERK-eIF2α-ATF4 stress axis; upregulation of ATF4, CHAC1, DDIT4, and DDIT3 was confirmed by qRT-PCR and/or Western blot analyses. Loratadine also reduced MDR1/P-glycoprotein expression. In vivo , loratadine suppressed tumor growth and enhanced paclitaxel efficacy without systemic toxicity. 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.