The miR-378a-3p/SLC7A11 axis mediates benzo[a]pyrene-induced ferroptosis in hippocampal neuronal cells

Ferroptosis, an iron-dependent form of regulated cell death, contributes to polycyclic aromatic hydrocarbon (PAH)-induced neurodegeneration. Benzo[a]pyrene (BaP), a neurotoxic polycyclic aromatic hydrocarbon, induces ferroptosis in neuronal cells, but the molecular mechanisms remain unclear. We examined the association between PAH exposure and SLC7A11 promoter methylation in human peripheral blood. Additionally, we employed molecular and genetic methods (RT-PCR, SLC7A11 knockdown/overexpression, and miR-378a-3p inhibition) to validate BaP-induced ferroptosis in HT22 neurons through the miR-378a-3p/SLC7A11 axis. The results indicated that high PAH exposure significantly reduced the average methylation level of the SLC7A11 promoter region, and BaP exposure induced ferroptosis in HT22 cells. Notably, SLC7A11 knockdown exacerbated ferroptosis, while SLC7A11 overexpression or miR-378a-3p inhibition attenuated ferroptosis. Our study therefore establishes the miR-378a-3p/SLC7A11 axis as a crucial mechanism in BaP-induced neuronal ferroptosis, providing a novel mechanistic insight into BaP-induced neurotoxicity. Targeting the miR-378a-3p/SLC7A11 pathway may mitigate environmental pollutant-induced neuronal damage in neurodegenerative diseases.