Combined exposure of alumina nanoparticles and chronic stress exacerbates hippocampal neuronal ferroptosis via activating IFN-γ/ASK1/JNK signaling pathway in rats

Alumina nanoparticles (AlNPs) exposure causes hippocampal-dependent cognitive dysfunction. However, whether chronic stress exacerbates AlNPs-induced hippocampal lesion and its mechanism remains unclear. This study was aimed to investigate the combined effects and mechanisms of AlNPs and chronic stress on the hippocampal lesion. The behavioral tests demonstrated that combined exposure to AlNPs and chronic restraint stress (CRS) worsened both cognition and depression-like behavior than exposed to AlNPs and CRS alone. Microstructural and ultrastructural observations showed that combined exposure to AlNPs and CRS exacerbated hippocampal damage. Both AlNPs and CRS induced hippocampal neuronal ferroptosis, presenting as iron and glutamate metabolism disorder, GPX4 fluorescence of neurons decrease, LPO and ROS levels increase, and FJB-positive neurons increase. Meanwhile, combined exposure to AlNPs and CRS exacerbated hippocampal neuronal ferroptosis. Mechanism investigation revealed that combined exposure to AlNPs and CRS activated IFN-γ/ASK1/JNK signaling pathway. Furthermore, IFN-γ neutralizing antibody R4–6A2 effectively inhibited the activation of IFN-γ/ASK1/JNK signaling pathway, alleviated hippocampal neuronal ferroptosis and improved cognition ability. ASK1 inhibitor GS-4997 also improved hippocampal neuronal ferroptosis and cognitive dysfunction by inhibiting ASK1/JNK signaling pathway. Together, these results demonstrate that combined exposure to AlNPs and CRS exacerbates hippocampal neuronal ferroptosis via activating IFN-γ/ASK1/JNK signaling pathway.