BPDE induces ferroptosis in hippocampal neurons through ACSL3 suppression.

Abstract

Benzo(a)pyrene (B[a]P) and its ultimate active metabolite, benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), are known to have neurotoxic effects that can damage hippocampal neurons and cause cognitive impairments. Ferroptosis, a form of programmed cell death distinct from apoptosis, is associated with multiple neurodegenerative conditions. Recently, we have found that BPDE triggers ferroptosis in hippocampal neurons, though the underlying molecular mechanism remains unclear. Here, we firstly identified ACSL3 as the target of BPDE-induced ferroptosis through transcriptomics, and then investigated its role in ferroptosis using gene transfection technology in HT22 cells and primary hippocampal neurons. Our results showed that BPDE treatment caused significant transcriptional changes in HT22 cells, notably decreasing ACSL3 expression, which was further validated in both HT22 cells and primary hippocampal neurons. Furthermore, overexpression of ACSL3 effectively rescued the ferroptosis induced by BPDE in HT22 cells and primary mouse hippocampal neurons, characterized by increased cell viability, enhanced glutathione and glutathione peroxidase activities, and reduced levels of intracellular free Fe²⁺, reactive oxygen species, and malondialdehyde. In summary, our findings demonstrated that BPDE induces ferroptosis in hippocampal neurons by inhibiting ACSL3 expression, providing new insights into the toxicological mechanisms underlying BPDE-induced neurotoxicity.