Transcriptomic analysis and experimental verification reveal the involvement of PI3K/AKT signaling pathway in high-altitude cognitive dysfunction [6_OHG]

Our Prior research has shown that 6-hydroxygenistein (6-OHG) alleviates hypobaric hypoxia induced brain injury (HHBI) achieved by its powerful antioxidant, anti-inflammatory, and anti-apoptotic capabilities, but its mechanism still requires additional investigation. The objective of this study was to uncover the protective mechanism of 6-OHG against HHBI based on transcriptomics analysis and experimental validation.The RNA-Seq analysis revealed 1585 differentially expressed genes (DEGs) between the Con and Mod groups, with 460 upregulated and 1125 downregulated. Between the 6-OHG and Mod groups, there were 679 DEGs, including 348 upregulated and 331 downregulated genes. Go and KEGG function analyses highlighted the PI3K/AKT signaling pathway as a crucial regulatory mechanism. Western blot analysis showed that HH exposure caused a decrease in the ratios of p-PI3K/PI3K and p-AKT/AKT in the mouse brain, but this effect was reversed by 6-OHG treatment, indicating that 6-OHG activates the PI3K/AKT signaling pathway. Furthermore, LY294002, a selective PI3K inhibitor, effectively blocked this activation and also abolished the protective effects of 6-OHG on histopathological damage, as well as its antioxidant, anti-inflammatory, and anti-apoptotic activities in HHBI mice. In summary, 6-OHG mitigates HHBI by activating the PI3K/AKT signaling pathway, suggesting its potential therapeutic application for HHBI treatment.