A new mechanism for ubiquitination in polystyrene nanoplastic-induced spatial cognitive dysfunction through microglial activation-induced apoptosis of neurons

Growing evidence indicates that nanoplastics (NPs), particularly polystyrene nanoparticles (PS-NPs), cross the blood-brain barrier and reach the hippocampus, where they induce neurotoxicity through oxidative stress, neuroinflammation, and synaptic damage. In the present study, we demonstrate that PS-NPs downregulate RNF139 in microglia, impairing the degradation of SCAP. Elevated SCAP levels trigger SREBP activation, disordered lipid metabolism, and enhanced lipid synthesis. Subsequently, mitochondrial dynamics are dysregulated, characterized by elevated mitochondrial reactive oxygen species, a drop in membrane potential, and diminished ATP synthesis. Under these pathological conditions, microglia become abnormally activated and secrete inflammatory factors such as TNF-α, IL-1β, and IL-6. This neuroinflammatory cascade induces neuronal damage and apoptosis, resulting in spatial cognitive impairment. Thus, our findings reveal a link between PS-NPs exposure, changes in microglial lipid metabolism, and nerve damage. They also identify targets for treating NP-induced neurological disorders.