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 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 protein-protein interaction 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-1α 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-1α 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-1α axis, thereby providing a novel therapeutic target for SAE.