STAT3/HIF1α axis promotes neuronal ferroptosis in sepsis-associated encephalopathy: based on transcriptomic analysis

Abstract Background This study aimed to provide novel insights for revealing the potential molecular mechanisms of ferroptosis in sepsis-associated encephalopathy (SAE). Methods Three independent SAE datasets were obtained from the GEO database. The differentially expressed genes (DEGs) were then intersected with ferroptosis-related markers. The intersected genes were further analyzed for the identification of ferroptosis-related DEGs (FRDEGs) and main pathways via protein-protein interaction (PPI) network construction and enrichment analysis. The related pathway targets were further verified at the mRNA and protein expression level. Results We demonstrated 121 highly expressed genes and 19 lowly expressed genes that play critical roles in SAE. Intersecting these DEGs with ferroptosis-related markers, we identified 11 FRDEGs. We constructed a PPI network of the 11 FRDEGs and found Stat3 showed the highest degree score. In addition, KEGG pathway analysis showed that the 11 FRDEGs were predominantly involved in HIF-1 signaling pathway. The results from animal experiments indicated that sepsis upregulated the mRNA and protein expression levels of Stat3/HIF-α axis in hippocampal tissue of SAE mice. In addition, we found that sepsis caused hippocampal ferroptosis, as evidenced by an increase in ferroptosis-related proteins and malondialdehyde, and a decrease in glutathione level. In contrast, treatment with Stat3 inhibitor attenuated hippocampal ferroptosis and decreased the mRNA and protein level of HIF-α in hippocampal tissue of SAE mice. Conclusion In conclusion, our study demonstrated that sepsis might induce the activation of hippocampal ferroptosis by triggering the Stat3/HIF-α axis, thereby providing a novel therapeutic target for SAE.