Ultrafine particles induce ferroptosis-like stress features in human dopaminergic LUHMES cells via the p53/xCT/GSH/cGPx4 axis.

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.