Copper oxide nanoparticles induce size dependent endothelial damage and cuproptosis via MAPK/NF-κB/NLRP3 signaling...

Copper oxide nanoparticles (CuO NPs) are widely used in agriculture, medicine, food, and electronic materials, raising increasing concerns about their potential health risks. Nanoparticles (NPs) can cross biological barriers and enter the bloodstream, making the cardiovascular system a potential target of toxicity. However, the endothelial toxicity of CuO NPs and the size dependent mechanisms underlying their effects remain unclear. In this study, the cytotoxicity of CuO NPs with different sizes in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms were investigated. CuO NPs reduced cell viability, increased LDH release, and inhibited cell proliferation in a size dependent manner (5 nm > 20 nm > 80 nm). Smaller CuO NPs induced higher ROS levels, disrupted the antioxidant system, and caused mitochondrial dysfunction, ultimately resulting in cuproptosis in HUVECs, as evidenced by DLAT aggregation and Fe-S proteins loss. In addition, CuO NPs activated the MAPK, NF-κB NLRP3 inflammasome and DNA damage response (DDR) pathway. Overall, CuO NPs induced size-dependent endothelial injury through oxidative stress, inflammation, DNA damage, and cuproptosis by activating MAPK/NF-κB/NLRP3 and the DDR pathway. These findings provide mechanistic insights into the cardiovascular toxicity of CuO NPs and support risk assessment of nanomaterial exposure.