ZnO nanoparticles induce developmental delay in Caenorhabditis elegans via SLC-30A9-mediated ferritinophagy-ferroptosis axis.

Zinc oxide nanoparticles (ZnO NPs) have been recognized as emerging contaminants, and their increasing environmental release has been verified to be associated with multiple adverse developmental consequences. However, data on the childhood stunting and the underlying mechanisms of ZnO NPs remain largely unclear. In this study, we employed Caenorhabditis elegans (C. elegans), a valuable animal model with high genetic similarity to humans, to explore the effects of ZnO NPs on larval development and reveal the subcellular mechanisms. Our findings showed that ZnO NPs significantly induced developmental delay, characterized by reduced body length/width and fertilized egg numbers (p < 0.05). Subcellular studies indicated that ZnO NPs markedly disturbed mitochondrial function, triggered excessive reactive oxygen species (ROS) production, activated ferritinophagy, and promoted ferroptosis. With the help of ferroptosis inhibitor ferrostatin-1, iron chelator deferoxamine, autophagy inhibitor chloroquine, and ROS scavenger catalase, we found that mitochondrial electron transport chain (ETC)-derived ROS triggered ferritinophagy-mediated ferroptotic cascade, leading to developmental delay when exposed to ZnO NPs. Notably, through RNAi-mediated silencing of slc-30a9 and the use of zinc chelator TPEN, the data further indicated that ZnO NPs downregulated the mitochondrial zinc exporter SLC-30A9, which served as the key initiating event in ROS accumulation. Overall, our results identify the SLC-30A9-mediated ferritinophagy-ferroptosis axis as a key mechanism driving ZnO NP-induced developmental delay, providing potential therapeutic targets for nanoparticle-related health disorders.