Copper oxide nanoparticles induce cuproptosis and ferroptosis through mitochondrial concatenation

Copper oxide nanoparticles (CuO NPs) will accumulate in soil and water due to human and natural activities, eventually finding their way into the human body through direct or indirect pathways. Therefore, it is crucial to study the biosafety of CuO NPs. CuO NPs primarily damage cells through CuO particles and copper ions, with intracellular copper ion overload being a critical factor in cuproptosis. However, the potential of CuO NPs to trigger cell cuproptosis has not been thoroughly investigated. While some studies have explored the relationship between cuproptosis and ferroptosis, the precise mechanism connecting the two remains unclear. Here, we have discovered that exposure to CuO NPs triggers cuproptosis in RAW264.7 cells. This process leads to the inhibition of mitochondrial membrane lipid synthesis, resulting in mitochondrial damage and disruption of intracellular redox balance, ultimately leading to ferroptosis. In vivo, both cuproptosis and ferroptosis were found to contribute to liver damage caused by CuO NPs, along with reduced lipid levels, mitochondrial impairment, and redox imbalance. In summary, our research contributes to the assessment of the biocompatibility of CuO NPs and offers additional insights into the mechanisms underlying cuproptosis. Our work suggested that cuproptosis serves as a key toxic mechanism of CuO NPs, damaging mitochondria to induce ferroptosis by disrupting mitochondrial membrane lipid synthesis.