Diquat exposure disrupts ferroportin-dependent iron homeostasis and drives ferroptosis-associated white matter injury.

Abstract

Diquat (DQ) is one of the most widely used bipyridyl herbicides and has been identified as a potential neurotoxin; however, its primary central nervous system (CNS) targets and the underlying mechanisms remain unclear. In cases of acute human DQ poisoning, subcortical white matter lesions have been reported to emerge approximately two weeks after exposure, with demyelination representing the predominant pathological finding. We used an acute oral DQ exposure rat model that mimics human DQ poisoning. Magnetic resonance imaging (MRI) revealed prominent white matter abnormalities in the corpus callosum, while histological analyses confirmed demyelination, impaired myelin integrity, reduced myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) expression, and marked mitochondrial ultrastructural damage. RNA sequencing indicated significant enrichment of ferroptosis-associated pathways. DQ induced sustained intracellular reactive oxygen species (ROS) accumulation and reduced nuclear factor erythroid 2-related factor 2 (Nrf2) expression. DQ exposure also reduced ferroportin (FPN) expression, accompanied by intracellular Fe2⁺ accumulation, enhanced lipid peroxidation, and ferroptotic cell death. In vivo, ferrostatin-1 pretreatment significantly attenuated DQ-induced demyelination. In vitro, N-acetylcysteine (NAC) partially restored Nrf2 expression and attenuated DQ-induced lipid peroxidation, whereas FPN overexpression reduced intracellular Fe2⁺ accumulation and lipid peroxidation. Collectively, these findings suggest that DQ disrupts redox balance and iron homeostasis in association with reduced Nrf2 signaling and FPN expression. Targeting FPN-mediated iron homeostasis warrants further investigation as a potential strategy for limiting DQ-induced neurotoxicity.