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

Figure 1 Central molecular mechanism of cuproptosis and mitochondrial protein lipoylation. Cuproptosis in gastrointestinal tumor cells is driven by mitochondrial copper accumulation and protein lipoylation. Cu²⁺ enters cells through copper transporters such as copper transporters/solute carrier family 31 member 1 and is reduced to Cu⁺ by ferredoxin 1 within mitochondria. Cu⁺ subsequently binds to lipoylated dihydrolipoamide S-acetyltransferase, inducing its oligomerization, Fe-S cluster protein loss, proteotoxic stress, and mitochondrial metabolic collapse, ultimately triggering caspase-independent cuproptotic cell death. CTR1: Copper transporters; SLC31A1: Solute carrier family 31 member 1; GC: Gastric cancer; CRC: Colorectal cancer; LIAS: Lipoic acid synthase; FDX1: Ferredoxin 1; DLAT: Dihydrolipoamide S-acetyltransferase; TCA: Tricarboxylic acid cycle; ETC: Electron transport chain.