Cuproptosis amplifier of copper-telaglenastat coordinate to trigger cell ferroptosis for synergistic breast cancer suppression

Metal ion homeostasis plays a pivotal role in maintaining cellular functions, and its disruption can initiate regulated cell death pathways. Despite its therapeutic potential, metal ion therapy for breast cancer has been hampered by inefficient ion delivery and the intrinsic resistance mechanisms of cancer cells. In this work, a cuproptosis amplifier of copper-telaglenastat coordinate (denoted as Cu-CB) is developed to trigger cell ferroptosis for synergistic breast cancer treatment. Telaglenastat (CB-839), a glutaminase inhibitor, is identified as an effective copper ionophore that facilitates the formation of Cu-CB. Specially, Cu-CB can promote the aggregation of lipoylated proteins to initiate cuproptosis, while also inhibiting glutathione (GSH) synthesis and downregulating glutathione peroxidase 4 (GPX4) to trigger ferroptosis. The interplay between these cuproptosis and apoptosis pathways, mediated by Cu-CB, significantly amplifies reactive oxygen species (ROS) production and lipid peroxidation, culminating in the synergistic suppression of breast cancer. Both in vitro and in vivo studies validate the superior antitumor effects of Cu-CB through the induction of cuproptosis and ferroptosis, which may provide a new insight for metal ion delivery systems and metal ion-based tumor therapies. A copper-telaglenastat coordinate is developed to promote the aggregation of dihydrolipoamide S -acetyltransferase (DLAT) to initiate cuproptosis, while inhibiting glutathione (GSH) synthesis and downregulating glutathione peroxidase 4 (GPX4) to trigger ferroptosis. The interplay between the cuproptosis and apoptosis pathways can significantly amplify reactive oxygen species (ROS) production and lipid peroxidation for synergistic breast cancer treatment.