Cuproptosis in gastric cancer: Mechanisms and therapeutic opportunities

Figure 1 This schematic provides an overview of systemic copper metabolism and the regulation of copper homeostasis in humans. During intestinal absorption, copper predominantly exists in the divalent form, Cu²⁺, and is then reduced to monovalent Cu⁺ by membrane-bound reductases, including members of the STEAP protein family, prior to cellular entry. Cu⁺ enters cells mainly through copper transporter 1/solute carrier family 31 member 1. After cellular uptake, copper is distributed by intracellular chaperones, including antioxidant 1 copper chaperone and copper chaperone for superoxide dismutase. This intracellular delivery supports superoxide dismutase 1-mediated antioxidant protection and contributes to mitochondrial respiration through cytochrome c oxidase assembly factors such as COX11, SCO1, and COX17. When intracellular copper becomes excessive, it is sequestered by glutathione and metallothioneins. ATPase copper-transporting alpha/beta mediates copper export and controls Golgi-associated trafficking, allowing copper incorporation into secreted cuproproteins such as ceruloplasmin. Disruption of copper homeostasis may enhance pathological angiogenesis and participate in tumorigenesis, tumor expansion, and metastatic spread. ATOX1: Antioxidant 1 copper chaperone; CCS: Superoxide dismutase; SOD1: Superoxide dismutase 1; GSH: Glutathione; MT: Metallothioneins; ATP7A/ATP7B: ATPase copper-transporting alpha/beta; CTR1: Copper transporter 1; SLC31A1: Solute carrier family 31 member 1. Created by FigDraw (Supplementary material).