EXPLORING THE PROGNOSTIC NECROPTOSIS-RELATED GENES AND UNDERLYING MECHANISM IN SEPSIS USING BIOINFORMATICS.

Abstract: Sepsis is a life-threatening disease due to a dysregulated host response to infection, with an unknown regulatory mechanism for prognostic necroptosis-related genes (NRGs). Using GEO datasets GSE65682 and GSE134347, we identified six NRG biomarkers ( ATRX , TSC1 , CD40 , BACH2 , BCL2 , and LEF1 ) with survival and diagnostic significance through Kaplan-Meier (KM) and receiver operating characteristic (ROC) analyses. Afterward, the ingenuity pathway analysis (IPA) highlighted enrichment in hepatic fibrosis pathways and BEX2 protein. Moreover, we examined their regulatory targets and functional links with necroptotic signaling molecules via miRDB, TargetScan, Network analyst, and GeneMANIA. The molecular regulatory network displayed that hsa-miR-5195-3p and hsa-miR-145-5p regulated ATRX, BACH2, and CD40, while YY1 showed strong connectivity, concurrently controlling LEF1, ATRX, BCL2, BACH2, and CD40. CD40 exhibited similar expression patterns to RIPK3 and MLKL, and LEF1 was functionally associated with MLKL. Additionally, DrugBank analysis identified paclitaxel, docetaxel, and rasagiline as potential BCL2-targeting sepsis treatments. Finally, real-time quantitative PCR confirmed ATRX, TSC1, and LEF1 downregulation in sepsis samples, contrasting CD40's increased expression in CTL samples. In conclusion, ATRX , TSC1 , CD40 , BACH2 , BCL2 , and LEF1 may be critical regulatory targets of necroptosis in sepsis, providing a basis for further necroptosis-related studies in sepsis.