Copper homeostasis imbalance and cuproptosis: Emerging targets and strategies for gastrointestinal tumor therapy

Figure 2 Metabolic reprogramming determines cuproptosis sensitivity. The Warburg phenotype promotes glycolysis, suppresses mitochondrial oxidative phosphorylation and the tricarboxylic acid cycle, and reduces ferredoxin 1/dihydrolipoamide S-acetyltransferase -dependent cuproptosis sensitivity. In contrast, metabolic rewiring by pyruvate dehydrogenase kinase inhibition, mitochondrial activation, or related interventions restores tricarboxylic acid cycle/oxidative phosphorylation activity and increases lipoylated protein accumulation. Under this respiratory state, copper ionophores such as elesclomol enhance copper toxicity and resensitize gastrointestinal tumor cells to cuproptosis. GLUT: Glucose transporter; HIF: Hypoxia-inducible factor; MCT: Monocarboxylate transporter; HK2: Hexokinase 2; PFKFB3: 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; TCA: Tricarboxylic acid cycle; OXPHOS: Oxidative phosphorylation; FDX1: Ferredoxin 1; DLAT: Dihydrolipoamide S-acetyltransferase; ATP: Adenosine triphosphate; ETC: Electron transport chain; PDK: Pyruvate dehydrogenase kinase.