YAP/TFRC/ALOXE3 signaling is involved in ferroptosis and neuroinflammation triggered by amino-functionalized graphene quantum dots

Recently, graphene quantum dots (GQDs) have been attracting extensive interests in a widespread application, but the little information on the risk assessments of GQDs could impose a restriction on their contributions in the neuroscience. In this study, the intranasal administration of amino group functionalized GQDs (A-GQDs) was observed to enhance the number of neuronal cell death, trigger ferroptosis activities, i.e. ferrous iron overload and lipid peroxidation as well as cause inflammatory reactions in hippocampus. Meanwhile, these adverse effects were found in BV2 microglial cells treated with A-GQDs, which were all attenuated by a ferroptosis-specific inhibitor ferrostain-1 (Fer-1). The inflammatory responses to A-GQDs in BV2 cells were evidenced as the increased secretion of pro-inflammatory cytokine TNF-α that was attributed to the high mobility group box 1 (HMGB1) released from ferroptosis-occurred cells. The nuclear transference of yes-associated protein (YAP), an effector in Hippo signaling pathway, regulated by the phosphorylation of p38 mitogen-activated protein kinase (MAPK) was then found to play a critical role in A-GQDs triggering ferroptosis through transcriptionally mediating transferrin receptor protein (TFRC) and arachidonate lipoxygenase 3 (ALOXE3) to increase levels of ferrous iron and lipid peroxides, respectively. The findings not only highlight the importance of risk assessments on QDs containing low toxic component, but also provide toxic biomarkers for the interventions of GQDs in the brain.