Acrylamide exposure induces neurotoxicity via the PI3K/Akt/NF-κB pathway: Evidence from network toxicology and...

Acrylamide (ACR) is a chemical compound widely used in industrial production and food processing, the underlying mechanisms of its neurotoxicity have yet to be fully elucidated. Through the integration of network toxicology, molecular docking, and experimental validation, this study systematically explored the underlying molecular mechanisms of ACR-induced neurotoxicity. Through database analysis, 183 ACR-related targets and 2725 neurotoxicity-associated targets were identified, among which 100 overlapping genes were predominantly enriched in the PI3K/Akt signaling pathway and apoptosis-related biological processes. Molecular docking and molecular dynamics simulations suggested potential interactions between ACR and key target proteins. While causing minimal alterations in peripheral organs, ACR exposure in vivo resulted in hippocampal neuronal disorganization and Nissl body loss, indicating potential neurotoxicity. In vitro studies demonstrated that ACR not only decreased cell viability in PC12 and HT22 cells but also significantly enhanced apoptosis and inflammation, while markedly activating the PI3K/Akt and NF-κB signaling pathway. The significant attenuation of these effects was observed following treatment with the PI3K inhibitor LY294002. These findings suggest that ACR-induced neurotoxicity involves the coexistence and imbalance of survival and inflammatory-apoptotic signaling, providing mechanistic insight into its neurotoxic effects and a theoretical basis for potential preventive strategies.