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

Oligomeric α-synuclein (α-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-1α pathway in α-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-1α in the ferroptosis of α-syn pathology has not been identified in vivo. In this study, above all, we successfully established α-syn-induced mouse models of Parkinson’s disease. Our immunohistochemistry results demonstrated that α-syn could activate IL6ST/STAT3/HIF-1α pathway in a model of α-syn-induced PD. We further conducted transcriptomic analysis on a mouse model of α-syn-induced PD, and GSEA revealed an association with ferroptosis. Consequently, we focused on investigating how α-syn might regulate the transcriptional activation of HSPB1. In conclusion, we determined the relationship between ferroptosis and the STAT3/HIF-1α pathway in α-syn-related pathology in vivo. Oligomeric α-syn could induce ferroptosis via the STAT3/HIF-1α signaling pathway. [Display omitted] •Oligomeric α-synuclein (α-syn) aggregation injection in striatum of mice can induce neuroinflammation and neurodegeneration in midbrain tissue of mice.•A decrease of IL6ST/JAK2/STAT3/HIF-1α pathway could lead to ferroptosis in α-syn-induced mice’s midbrain tissue .•α-syn could regulate the transcriptional activation of HSPB1, which might be involved in the STAT3/HIF-1α signaling pathway related ferroptosis in α-syn-induced mice model.•The over-expression of Fe2+ and ROS in a-syn-induced BV2 cells could be reserved when treated with STAT3 inhibitor, which indicated the relationship between STAT3/HIF-1α pathway and ferroptosis in α-syn-induced cellular model.