USP18 suppresses dopaminergic neuronal ferroptosis in Parkinson’s disease through regulation of SLC7A11

Ferroptosis-driven dopaminergic neuronal loss is recognised as a key pathological mechanism in the onset and progression of Parkinson’s disease (PD), with SLC7A11–a core subunit of the Xc⁻ system–playing a pivotal role in this process. However, its upstream regulatory factors remain unclear. Here we show that USP18 is significantly downregulated in both MPTP/MPP⁺ models of PD and patient-derived datasets. Overexpression of USP18 mitigates dopaminergic neuronal loss, synaptic structural damage, and neurobehavioural deficits. Multi-omics analysis identifies USP18 as a key regulator of ferroptosis in PD, with SLC7A11 as its primary downstream effector. Mechanistically, USP18 maintains SLC7A11 homeostasis through dual pathways: it directly binds and deubiquitinates SLC7A11, thereby stabilising its protein levels, while simultaneously downregulating the transcription factor ATF3, thereby releasing its inhibitory control over the SLC7A11 promoter. This establishes a ‘USP18–ATF3–SLC7A11’ regulatory axis that reduces neuronal susceptibility to ferroptosis. Consistently, USP18 expression is positively correlated with SLC7A11 expression in the substantia nigra of PD patients. Overall, our results identify USP18 for the first time as a key regulator of ferroptosis in PD and reveal the central role of the USP18–SLC7A11 axis in dopaminergic neuronal loss, suggesting that USP18 holds promise as a potential therapeutic target for PD intervention.