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).

Figure 2 Proposed model of cuproptosis. Cuproptosis refers to a mitochondria-related, copper-dependent form of regulated cell death. Elesclomol, acting as a copper ionophore, facilitates intracellular copper accumulation, whereas ferredoxin 1 catalyzes the conversion of Cu²⁺ into Cu⁺. Increased Cu⁺ levels enhance lipoylation-dependent interactions and drive the aggregation of lipoylated proteins associated with the tricarboxylic acid cycle, especially dihydrolipoamide S-acetyltransferase (DLAT), thereby triggering proteotoxic stress. At the same time, copper-mediated stress impairs the stability of iron-sulfur (Fe-S) cluster proteins and accelerates their depletion, which in turn activates mitochondrial stress responses. Collectively, the accumulation of aggregated lipoylated DLAT together with the loss of Fe-S cluster proteins represents a defining molecular hallmark of cuproptosis. This mode of cell death is independent of reactive oxygen species and generally cannot be blocked by antioxidants, except for glutathione, which attenuates cuproptosis through copper chelation. ES: Elesclomol; FDX1: Ferredoxin 1; TCA: Tricarboxylic acid; DLAT: Dihydrolipoamide S-acetyltransferase; Fe-S: Iron-sulfur; ROS: Reactive oxygen species; GSH: Glutathione. Created by FigDraw (Supplementary material).