A Copper(I)-Azurin Complex Suppresses p53-Mediated Glycolysis to Sensitize Breast Cancer to Cuproptosis with MRI Monitoring.

The Warburg effect drives cancer cells to rely preferentially on glycolysis, resulting in diminished mitochondrial oxidative phosphorylation (OXPHOS). This metabolic phenotype limits the ability of excess copper (Cu) ions to trigger cuproptosis in dysfunctional mitochondria, leading to suboptimal therapeutic outcomes. Therefore, remodeling tumor energy metabolism to counteract the Warburg effect represents a pivotal strategy to enhance cuproptosis efficacy. Herein, we developed a Cu(I)-stabilized metal-organic framework nanoplatform (CuTz-1) encapsulated by Azurin (CuTz-1@Azurin) as a cuproptosis sensitizer. Mechanistically, Azurin increases p53 protein levels by intercepting MDM2-mediated ubiquitin-proteasome degradation. Elevated p53 subsequently inhibits pyruvate kinase M2 (PKM2) activity, suppressing glycolysis, while simultaneously promoting mitochondrial OXPHOS-collectively shifting cellular metabolism from glycolysis toward mitochondrial respiration and sensitizing tumor cells to Cu-induced proteotoxic stress. In addition, CuTz-1@Azurin triggers oxidative stress via reactive oxygen species (ROS) generation and glutathione (GSH) depletion, which act together with p53-mediated apoptosis to suppress tumor growth. Meanwhile, the oxidation of Cu(I) to paramagnetic Cu(II) enables real-time monitoring of the therapeutic process by magnetic resonance imaging (MRI). Both in vitro and in vivo results demonstrate good antitumor performance of CuTz-1@Azurin. This study highlights the potential of Azurin-mediated metabolic regulation as a promising strategy to potentiate cuproptosis for combined cancer therapy.