Nicotinamide Mononucleotide Ameliorates Nano‐Aluminum Oxide‐Induced Cognitive Impairment and Ferroptosis via the GSH/GPX4 Axis

ABSTRACT Aluminum oxide nanoparticles (Nano‐Al ₂ O ₃ ) are widely used engineered nanomaterials, but their neurotoxic effects and underlying mechanisms remain incompletely understood. Nicotinamide mononucleotide (NMN), a precursor to nicotinamide adenine dinucleotide (NAD), possesses antioxidant properties and neuroprotective potential. In this study, we investigated whether NMN mitigates Nano‐Al ₂ O ₃ ‐induced cognitive impairment and neuronal injury, with a focus on ferroptosis‐related pathways. Behavioral tests demonstrated that Nano‐Al ₂ O ₃ exposure impaired learning and memory in mice. Histological and ultrastructural analyses revealed hippocampal neuronal loss, reduced Nissl body density, and mitochondrial abnormalities, all of which were alleviated by NMN treatment. Nano‐Al ₂ O ₃ exposure also increased lipid peroxidation, malondialdehyde, Fe ²⁺ , and reactive oxygen species, while decreasing NAD ⁺ , glutathione (GSH), and glutathione peroxidase 4 (GPX4), indicating ferroptosis‐related damage. NMN largely reversed these alterations, restored redox homeostasis, and improved cognitive performance. Collectively, these findings suggest that Nano‐Al ₂ O ₃ ‐induced neurotoxicity is associated with dysregulation of the GSH/GPX4 axis and that NMN protects against cognitive impairment and neuronal injury, at least in part, by suppressing ferroptosis‐related processes. These findings suggest that Nano‐Al ₂ O ₃ ‐induced neurotoxicity is associated with dysregulation of the GSH/GPX4 axis and that NMN protects against cognitive impairment and neuronal injury, at least in part, by suppressing ferroptosis‐related processes.