Discovery of Natural Resorcylic Acid Lactones as Novel Potent Copper Ionophores Covalently Targeting PRDX1 to Induce Cuproptosis for Triple-Negative Breast Cancer Therapy

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer. Cuproptosis, a novel identified cell death form, is triggered by the direct binding of copper to lipoylated components of the tricarboxylic acid cycle. Identifying new effective drug targets and copper ionophores inducing cuproptosis for TNBC therapy is an urgent clinical need. In this study, a total of 24 resorcylic acid lactones (RALs, <b>1</b>-<b>24</b>), including 9 previously unreported ones, were isolated from the endophyte <i>Ilyonectria</i> sp. Various assays demonstrated that pochonin D (<b>16</b>, PoD) effectively inhibited the proliferation of TNBC cells <i>in vivo</i> and <i>in vitro</i>. Further investigations, including transcriptomics, proteomics, bioinformatics analysis, CMap, OTTER, clinical samples, and the use of PoD as molecular probe, revealed that PRDX1 is associated with cuproptosis and served as a potential target in TNBC. Mechanistically, PRDX1 was involved in the process of cuproptosis, and PoD bound to the Cys173 site of PRDX1, inhibited its enzymatic activity, and intervened with cuproptosis, thereby exerting anti-TNBC activity. Our study revealed that PRDX1 is not only a promising biomarker associated with cuproptosis but also a therapeutic target for TNBC, and PoD is a novel copper ionophore capable of inducing cuproptosis in TNBC cells by targeting PRDX1.