Ultrafine particles induce ferroptosis-like stress features in human dopaminergic LUHMES cells via the...

Parkinson's disease (PD) involves progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta, with regulated cell death (RCD) pathways - ferroptosis and apoptosis - contributing to neurodegeneration. Ferroptosis, an iron-dependent form of oxidative cell death, was evaluated here in human dopaminergic neurons exposed to urban industrial ultrafine particles (UFP) from Dunkirk. Differentiated LUHMES cells were treated with 2 or 10 μg/cm² UFP for 24 h, for comparison, cells received 5 μM MPP⁺, a reference PD toxin. UFP exposure caused reductions in cytosolic GPx4 and the GSH/GSSG ratio, and increased oxidative damage and electrophilic stress (4-HNE); neither TfR nor DMT1 expression nor ferritin levels changed. Mechanistically, UFP activated p53, downregulating xCT and compromising GSH synthesis, thereby driving ferroptosis-like stress. By contrast, MPP⁺ induced more pronounced oxidative imbalance, elevated GSSG, and activated both intrinsic (BAX, caspase-9) and extrinsic (caspase-8) apoptotic cascades. These findings constitute the first evidence that environmentally relevant UFP concentrations trigger ferroptosis-like stress features in human dopaminergic neurons. They implicate chronic UFP inhalation as a potential modifiable risk factor in PD pathogenesis.