Ag₂Se quantum dots neurotoxicity: mitochondrial stress drives ferroptosis-dependent microglial inflammation

Silver Selenide quantum dots (Ag₂Se QDs) have great potential for biomedical applications due to their excellent optical properties, which has raised concerns about their health hazards. Previous studies have shown that exposure to Ag₂Se QDs can induce neurotoxicity, but the underlying mechanisms have not been fully elucidated. In this study, Ag₂Se QDs activated Nod-like receptor protein 3 (NLRP3) inflammasomes in microglia. Interestingly, we found that Ag₂Se QDs-induced NLRP3 inflammasome activation was ferroptosis-dependent. Mechanistically, the overproduction of mitochondrial reactive oxygen species (mtROS) led to the leakage of mitochondrial DNA (mtDNA) into the cytoplasm via the open mitochondrial permeability transition pore (mPTP), thereby activating stimulator of interferon genes (STING)-dependent ferritinophagy. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy resulted in the degradation of ferritin heavy chain 1 (FTH1) and the release of iron ions, ultimately triggering ferroptosis. In order to assist in the risk assessment of Ag₂Se QDs and the development of risk management strategies. Based on the above experimental data, we constructed an Adverse Outcome Pathway (AOP) framework for Ag₂Se QDs neurotoxicity and emphasized the significance of alleviating mitochondrial damage in preventing neurotoxicity. Overall, the present study reveals new mechanisms of Ag₂Se QDs-induced neurotoxicity. Meanwhile, this study provides insightful references for toxicity assessment and address.