Systematic analysis based on bioinformatics and experimental validation identifies as a novel therapeutic target of quercetin for sepsis.

PURPOSE

This study investigated the molecular mechanism of quercetin in the treatment of sepsis using network pharmacological prediction and experimentation.

METHODS

Hub genes were identified by intersecting the differentially expressed genes (DEGs) of the GSE131761 and GSE9960 databases with genes from the hub modules of Weighted Gene Co-Expression Network Analysis (WGCNA), targets of quercetin, and ferroptosis. Subsequently, in order to determine the functional characteristics and molecular link of hub gene obtained above, we redetermined the hub-DEGs in GSE131761 according to high or low hub gene expression. Afterward, the main pathways of enrichment analysis were validated using these hub-DEGs. Finally, an experiment was conducted to validate the findings.

RESULTS

By intersecting 1415 DEGs in GSE131761, 543 DEGs in GSE9960, 5784 key modular genes, 470 ferroptosis-related genes, and 154 quercetin-related genes, we obtained one quercetin-related gene, . Subsequently, 340 hub-DEGs were further validated according to high or low expression. The results of the enrichment analysis revealed that hub-DEGs were mainly associated with inflammation and the immune response. Immune infiltration analysis showed that higher expression of was related to macrophage infiltration and could be a predictor of diagnosis in patients with sepsis. The expression pattern of was then depicted and the upregulation of in the vital organs of septic mice was further demonstrated. and experiments showed that upregulation of and inflammation-related cytokines induced by sepsis could be inhibited by quercetin ( < 0.05).

CONCLUSIONS

may be involved in the occurrence and development of multi-organ functional disturbances in sepsis and is a reliable target of quercetin against sepsis.