FOXO1 inhibition attenuates ferroptosis-like changes and apoptosis in dopaminergic neurons with the involvement of the SREBP1/SCD1 axis in Parkinson's disease.

Oxidative damage-triggered ferroptosis and apoptosis drive the progression of Parkinson's disease (PD). Forkhead box O1 (FOXO1) is a critical modulator of oxidative stress, while its role in PD remains largely unexplored. Here, the FOXO1 inhibitor AS1842856 (AS) was employed to treat the MPTP-exposed mice and MPP+-challenged SH-SY5Y cells. MPTP/MPP+ markedly upregulated FOXO1 expression and enhanced its transcriptional activity, effects that were significantly abrogated by AS treatment. Importantly, AS treatment rescued the MPTP/MPP+-induced downregulations of sterol regulatory element-binding protein 1 (SREBP1) and stearoyl-CoA desaturase-1 (SCD1), accompanied by reduced oxidative damage, resulting in reduced ferroptosis-like changes and caspase-3-mediated apoptosis in both in vivo and in vitro models. Finally, AS treatment effectively ameliorated MPTP-induced motor deficits in mice. Collectively, these findings show that FOXO1 inhibition alleviates PD pathology by suppressing ferroptosis-like changes and apoptosis in dopaminergic neurons via a mechanism involving the SREBP1/SCD1 axis, suggesting FOXO1 as a promising therapeutic target for PD.