Elucidating the toxicological impact and mechanism of plasticizers exposure on Alzheimer's disease through network toxicology and molecular docking.

This study aimed to explore the underlying mechanisms and key targets of widely used plasticizers, including dimethyl phthalate (DMP), diethyl phthalate (DEP), and dioctyl phthalate (DOP), in the pathogenesis of Alzheimer's disease (AD). Network toxicology, molecular docking, and dynamics simulation screened candidate targets for plasticizer in increasing AD risk. Three machine learning algorithms and two microarray datasets identified key targets, whose immune relevance was assessed by CIBERSORT. An Aβ42-induced BV2 microglia model validated their role. We identified 83 plasticizer targets relevant to AD, which were enriched in KEGG pathways like apoptosis and neuroactive ligand-receptor interaction. CDK5, SLC2A1, and STAT3 were confirmed as key targets, showing consistent differential expression in two AD datasets. Their expression correlated with M1 macrophage infiltration. Molecular docking and dynamics simulations demonstrated that plasticizers stably bind these targets with high affinity. In Aβ42-induced BV2 microglia, phthalate treatment elevated inflammatory factors (TNF-α, IL-1β, IL-6) and STAT3 expression. This study demonstrated the possible mechanistic associations between plasticizers exposure and AD, and STAT3 might be the key target of plasticizers.