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.