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Repurposing antihistamine to chemotherapy via a molecular delivery platform co-targeting mitochondria and endoplasmic reticulum

Authors: WANG Ling-Li; ZHENG Ming-Hua; JIN Jing-Yi; ZHU Shoujun; ZHANG Songling

DOI: 10.1007/s40843-025-3447-4Status: Verified Translated Edition
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Key Findings in This Report

• • DDY reduced pulmonary metastatic nodules to 2.4 per lung versus 21 in controls and 6.6 for free desloratadine in a 4T1 orthotopic breast tumor model (p < 0.01), demonstrating a >8-fold suppression of metastasis; this matters clinically because metastasis, not primary tumor size, drives mortality in triple-negative breast cancer. • • Immunohistochemical analysis showed drastic decreases in SLC7A11 and GPX4 levels in DDY-treated tumors, confirming ferroptosis as the mechanism of action; this provides a biomarker strategy for patient selection and suggests combination with ferroptosis inducers may overcome resistance. • • DDY exhibited selective toxicity against MCF-7, MDA-MB-231, and 4T1 tumor cells at concentrations up to 20.0 μM, while sparing normal MCF-10A breast cells; this selectivity index is critical for reducing off-target toxicity and enabling dose escalation in vivo. • • DDY administration significantly inhibited tumor growth to the smallest tumor volume and weight among groups and suppressed distal liver metastasis, with no significant effect on mouse body weight; this indicates a favorable therapeutic window and potential for chronic dosing in metastatic settings.