Cuproptosis in gastric cancer: Mechanisms and therapeutic opportunities

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).