Cuproptosis, a novel form of copper-induced cell death, has emerged as a significant area of research in cancer biology and therapeutics. This review explores the systemic and cellular metabolism of copper, including its influence on tumor-related signaling pathways. The discovery of cuproptosis challenges traditional understandings of cell death mechanisms and suggests a new paradigm for cancer treatment by targeting copper metabolism. Key aspects include: 1. **Copper Metabolism and Homeostasis**: Copper plays a crucial role in various cellular processes, including energy metabolism and antioxidant defense. The review discusses the intricate mechanisms of copper absorption, transport, and efflux, highlighting the importance of copper chaperones and transporters like ATP7A and ATP7B. 2. **Copper Uptake and Utilization**: The process of copper uptake and utilization within cells is detailed, emphasizing the roles of copper chaperones such as CCS and ATOX1. These chaperones facilitate the distribution of copper to different cellular compartments, including mitochondria, where it is essential for oxidative phosphorylation. 3. **Copper Export and Regulation**: The regulation of copper export through transporters like ATP7A and ATP7B is discussed, along with the role of metallothioneins in maintaining copper homeostasis. The review also explores the impact of copper dysregulation on cancer development, particularly in various types of cancers. 4. **Molecular Mechanisms of Cuproptosis**: The molecular mechanisms of cuproptosis, involving the interaction of copper ions with lipoacylated components in the TCA cycle, leading to protein aggregation and cellular stress, are explained. Key proteins like Ferredoxin 1 (FDX1) and dihydrolipoamide S- acetyltransferase (DLAT) play critical roles in this process. 5. **Cuproptosis and Other Cell Death Pathways**: The review discusses the relationship between cuproptosis and other known cell death pathways such as necroptosis, pyroptosis, and ferroptosis. It highlights how cuproptosis can be a unique vulnerability in cancer cells, offering potential therapeutic targets. 6. **Cancer Development and Cuproptosis**: The role of copper dysregulation in cancer development is explored, including its impact on tumor progression, cell proliferation, metastasis, and resistance to chemotherapy. The review also examines the interplay between cuproptosis and other signaling pathways, such as the PI3K-AKT and MAPK pathways. 7. **Therapeutic Implications**: The review suggests potential cancer treatments using copper ionophores that induce cuproptosis, combined with small molecule drugs, for precision therapy in specific cancer types. It emphasizes the need for further research to fully understand the mechanisms of cuproptosis and to develop effective therapeutic strategies. Overall, the review underscores the significance of cuproptosis in cancer biology and highlights its potential as a novelCuproptosis, a novel form of copper-induced cell death, has emerged as a significant area of research in cancer biology and therapeutics. This review explores the systemic and cellular metabolism of copper, including its influence on tumor-related signaling pathways. The discovery of cuproptosis challenges traditional understandings of cell death mechanisms and suggests a new paradigm for cancer treatment by targeting copper metabolism. Key aspects include: 1. **Copper Metabolism and Homeostasis**: Copper plays a crucial role in various cellular processes, including energy metabolism and antioxidant defense. The review discusses the intricate mechanisms of copper absorption, transport, and efflux, highlighting the importance of copper chaperones and transporters like ATP7A and ATP7B. 2. **Copper Uptake and Utilization**: The process of copper uptake and utilization within cells is detailed, emphasizing the roles of copper chaperones such as CCS and ATOX1. These chaperones facilitate the distribution of copper to different cellular compartments, including mitochondria, where it is essential for oxidative phosphorylation. 3. **Copper Export and Regulation**: The regulation of copper export through transporters like ATP7A and ATP7B is discussed, along with the role of metallothioneins in maintaining copper homeostasis. The review also explores the impact of copper dysregulation on cancer development, particularly in various types of cancers. 4. **Molecular Mechanisms of Cuproptosis**: The molecular mechanisms of cuproptosis, involving the interaction of copper ions with lipoacylated components in the TCA cycle, leading to protein aggregation and cellular stress, are explained. Key proteins like Ferredoxin 1 (FDX1) and dihydrolipoamide S- acetyltransferase (DLAT) play critical roles in this process. 5. **Cuproptosis and Other Cell Death Pathways**: The review discusses the relationship between cuproptosis and other known cell death pathways such as necroptosis, pyroptosis, and ferroptosis. It highlights how cuproptosis can be a unique vulnerability in cancer cells, offering potential therapeutic targets. 6. **Cancer Development and Cuproptosis**: The role of copper dysregulation in cancer development is explored, including its impact on tumor progression, cell proliferation, metastasis, and resistance to chemotherapy. The review also examines the interplay between cuproptosis and other signaling pathways, such as the PI3K-AKT and MAPK pathways. 7. **Therapeutic Implications**: The review suggests potential cancer treatments using copper ionophores that induce cuproptosis, combined with small molecule drugs, for precision therapy in specific cancer types. It emphasizes the need for further research to fully understand the mechanisms of cuproptosis and to develop effective therapeutic strategies. Overall, the review underscores the significance of cuproptosis in cancer biology and highlights its potential as a novel