Advances in the Neurotoxic Mechanisms of Acrylamide and Multitarget Intervention Strategies of Natural Products

ABSTRACT

Acrylamide (AA) is a widespread environmental and food‐processing contaminant that causes progressive nervous system damage following chronic exposure. Here, we integrate the latest evidence on the sources, metabolic pathways, and interconnected neurotoxic mechanisms of AA. AA‐induced neurotoxicity arises from a network of interconnected processes: presynaptic injury and axon degeneration, oxidative stress and mitochondrial dysfunction, dysregulation of apoptosis and autophagy, ferroptosis, inflammasome‐mediated pyroptosis, and disruption of the microbiota–gut–brain axis. Given the lack of specific therapies, natural products from diverse chemical classes, including flavonoids, phenolic acids, terpenoids, alkaloids, polysaccharides, and prebiotics, have shown multitarget protective effects. Despite these advances, critical barriers persist, including mechanistic complexity, poor oral bioavailability, limited blood–brain barrier penetration and model system limitations. To overcome these challenges, further research will need to incorporate multiomics technology, human‐relevant organoid systems, and brain delivery systems into future studies of the clinical application of natural product therapy for neurodegenerative diseases caused by AA.