Multifunctional platinum(IV) complexes reverse cisplatin resistance in triple- negative breast cancer via ferroptosis and apoptosis.

Platinum(II) drugs are important chemotherapeutical strategies for the triple-negative breast cancer (TNBC) but are frequently hindered by resistance and systematic toxicity. To address these limitations, a series of novel platinum(IV) complexes were designed by integrating ferroptosis inducers (sulfasalazine derivatives) with platinum-based moieties. Among them, complex 11 emerged as the most effective agent against both cisplatin (CDDP)-sensitive and CDDP-resistant TNBC cell lines, but showed lower cytotoxicity toward the normal breast epithelial cell line MCF-10 A compared with CDDP or carboplatin. Mechanistic studies revealed that the enhanced cellular uptake of 11 efficiently induced DNA damage, and activated the mitochondria-dependent apoptotic pathway. Furthermore, 11 significantly promoted the accumulation of lipid peroxides, downregulated glutathione peroxidase 4 and solute carrier family 7 member 11 expression levels, and induced characteristic mitochondrial morphological alterations, thereby triggering ferroptosis. In vivo, 11 exhibited potent antitumor efficacies without causing significant toxicity. Collectively, this study presents a promising strategy for TNBC treatment by integrating chemotherapy with ferroptosis within a single molecular entity.