Involvement of the STAT3/HIF-1α signaling pathway in α-synuclein-induced ferroptosis

Oligomeric alpha-synuclein (alpha-syn) aggregates, which are a critical pathological feature of Parkinson's disease (PD), can induce neuroinflammation and neurodegeneration. Our previous study revealed a decrease in IL6ST/JAK2/ STAT3/HIF-1 alpha pathway in alpha-syn-induced microglia. As we all know, the JAK2/STAT3 signaling pathway is essential for modulating inflammation, controlling cell growth and exhibiting antiapoptotic responses. However, the precise role of STAT3/HIF-1 alpha in the ferroptosis of alpha-syn pathology has not been identified in vivo. In this study, above all, we successfully established alpha-syn-induced mouse models of Parkinson's disease. Our immunohistochemistry results demonstrated that alpha-syn could activate IL6ST/STAT3/HIF-1 alpha pathway in a model of alpha-syn-induced PD. We further conducted transcriptomic analysis on a mouse model of alpha-syn-induced PD, and GSEA revealed an association with ferroptosis. Consequently, we focused on investigating how alpha-syn might regulate the transcriptional activation of HSPB1. In conclusion, we determined the relationship between ferroptosis and the STAT3/HIF-1 alpha pathway in alpha-syn-related pathology in vivo. Oligomeric alpha-syn could induce ferroptosis via the STAT3/HIF-1 alpha signaling pathway.