Plin4 modulates lipid droplet accumulation and ferroptosis in neurons exposed to benzo[a]pyrene

Abstract Benzo[a]pyrene (B[a]P), an environmental neurotoxin, induces cognitive decline through ferroptosis-mediated mechanisms. Transcriptomic analysis (GSE75206) of B[a]P-exposed mouse hippocampus identified 1668 differentially expressed genes, with Plin4 emerging as a key regulator linked to ferroptosis and lipid droplet (LD) accumulation. Behavioral tests confirmed hippocampal-dependent cognitive impairment and Plin4 upregulation. Molecular analyses demonstrated ferroptosis activation, evidenced by altered expression of related genes ( Gpx4 , Slc7a11 , Ptgs2 ) and biochemical markers of lipid peroxidation and iron imbalance. In HT22 cells, Benzopyrene-7,8-Diol-9,10-Epoxide (BPDE) dose-dependently elevated Plin4 expression, inducing mitochondrial damage and ferroptosis. Silencing Plin4 reversed BPDE-induced ferroptosis by restoring redox balance, reducing LD accumulation, and improving mitochondrial integrity. Mechanistically, Plin4 amplifies B[a]P neurotoxicity by exacerbating iron overload and LD accumulation, sensitizing neurons to ferroptosis. This study identifies Plin4 as a central mediator of environmental pollutant-induced neurodegeneration and proposes it as a therapeutic target for ferroptosis-related cognitive disorders.