STAT3-mediated ferroptosis is involved in α-synuclein pathology

AbstractBackgroundOligomeric α-synuclein (α-syn) can activate microglia to drive the early stages of Parkinson's disease (PD) pathogenesis. Our previous studies have found a significant expression difference between the lncRNA IL6ST-AS and its antisense RNA IL6ST in the cerebrospinal fluid of PD patients. Furthermore, in α-syn-induced HMC3 cells, a decline in IL6ST and its downstream target JAK2/STAT3 were also observed. Accumulating investigations have illustrated that STAT3 regulates the expression of ferroptosis-related genes and further influences the proliferation of cells.MethodsThe role and mechanisms of IL6ST/JAK2/STAT3 axis in α-syn induced HMC3 cells and PD mouse models were explored by Western blot or immunohistochemistry. Transcriptome sequencing of HMC3 cells exposed to α-syn oligomers and PD mouse models were performed. The STAT3 activator and the STAT3 inhibitor were used to regulate the expression of STAT3. qPCR was used to detect the expression of ferroptosis regulation genes (FRG) in HMC3 cells induced by α-syn or STAT3 inhibitor. ROS, lipid peroxidation and iron levels were measured by flow cytometry.ResultsWe found that α-syn could impair cell activity and stalely inhibit the IL6ST/ STAT3/HIF-1α pathway in α-syn-induced HMC3 cells. Besides, we performed transcriptomic analysis for α-syn-induced HMC3 cells and in α-syn-induced PD mouse models and GSEA indicated an association with ferroptosis. The reduction in P-STAT3 resulted in the lower expression of HIF-1α and the transcriptional activation of ferroptosis positive regulation (FPR) genes. P-STAT3 mediated ferroptotic cell death in α-syn-induced HMC3 cells by modulating lipid peroxidation and iron metabolism levels. An in vivo study revealed that the IL6ST/JAK2/STAT3/HIF-1α pathway was upregulated in PD mouse models.ConclusionsSTAT3 was an important factor that regulates ferroptosis in α-syn pathology via the JAK2/STAT3/HIF-1α axis. Our research illustrated the relationship of the JAK2/STAT3/HIF-1α axis and ferroptosis in the pathological process of α-syn both in vitro and in vivo, providing new topics of interest regarding the inflammation damage hypothesis and pathogenesis in PD.