Cuproptosis: Mechanisms, biological significance, and advances in disease treatment-A systematic review

Abstract

Background: Copper is an essential trace element for biological systems, as it plays a critical role in the activity of various enzymes and metabolic processes. However, the dysregulation of copper homeostasis is closely associated with the onset and progression of numerous diseases. In recent years, copper-induced cell death, a novel form of cellular demise, has garnered significant attention. This process is characterized by the abnormal accumulation of intracellular copper ions, leading to cellular dysfunction and eventual cell death. Copper toxicity occurs through the interaction of copper with acylated enzymes in the tricarboxylic acid (TCA) cycle. This interaction results in subsequent protein aggregation, causing proteotoxic stress and ultimately resulting in cell death. Despite the promise of these findings, the detailed mechanisms and broader implications of cuproptosis remain underexplored. Therefore, our study aimed to investigate the role of copper in cell death and autophagy, focusing on the molecular mechanisms of cuproptosis. We also aimed to discuss recent advancements in copper-related research across various diseases and tumors, providing insights for future studies and potential therapeutic applications.

Main body: This review delves into the biological significance of copper metabolism and the molecular mechanisms underlying copper-induced cell death. Furthermore, we discuss the role of copper toxicity in the pathogenesis of various diseases, emphasizing recent advancements in the field of oncology. Additionally, we explore the therapeutic potential of targeting copper toxicity.

Conclusion: The study highlights the need for further research to explore alternative pathways of copper-induced cell death, detailed mechanisms of cuproptosis, and biomarkers for copper poisoning. Future research should focus on exploring the molecular mechanisms of cuproptosis, developing new therapeutic strategies, and verifying their safety and efficacy in clinical trials.

Keywords: apoptosis; autophagy; cancer; cell death; copper; cuproptosis; tricarboxylic acid cycle.

FIGURE 1

The metabolic pathway of copper within cells is a finely regulated process. Cu²⁺ from outside the cell can enter the cell through passive diffusion. Inside the cell, the reductase FDX1 can reduce Cu²⁺ to Cu⁺. Additionally, Cu²⁺ outside the cell can be reduced to Cu⁺ by the reductase STEAP and then transported into the cell with the assistance of CTR1. Within the cell, copper chaperones such as ATOX1, CCS, and SOD1 bind to copper ions and transport them to specific organelles to perform their biological functions. In the mitochondria, the protein COX17 transports copper ions from the cytoplasm to the mitochondrial inner membrane, where they are subsequently passed on to mitochondrial membrane proteins (SCO1 and SCO2) as well as COX11, ultimately combining with cytochrome c oxidase (CCO) to participate in the electron transport chain. In the cell's trans‐Golgi network (TGN), ATP7A and ATP7B are two important copper‐transporting ATPases that regulate the excretion of copper to maintain the homeostasis of intracellular copper ions. The coordinated action of these chaperones and transport proteins ensures the rational distribution and functional expression of copper ions within the cell while also preventing cytotoxicity that excess copper ions may cause.

FIGURE 2

Cuproptosis is a complex process involving various molecular mechanisms. Initially, copper ions are absorbed into the cell through the mediation of the SLC31A1 protein. Subsequently, the ATP7A/B proteins transport copper ions from inside the cell to the outside, maintaining the homeostasis of copper ions. In this process, the FDX1 protein plays a crucial role. FDX1 reduces Cu²⁺ to Cu⁺, thereby promoting the process of palmitoylation of the DLAT protein. The binding of copper ions to palmitoylated proteins leads to their aggregation and loss of normal function, ultimately triggering cell death. Additionally, FDX1 is involved in the loss of iron–sulfur cluster proteins, which damages mitochondrial function and further induces cell death. Meanwhile, the binding of copper ions to the CCS protein triggers the succinylation of the SOD1 protein, which weakens the ability of SOD1 to clear reactive oxygen species (ROS). Excessive accumulation of ROS within the cell negatively affects the cell's tricarboxylic acid cycle (TCA cycle), ultimately leading to cell death.