The role of four ERS-related key genes in sepsis induced organ dysfunction and the forewarning model construction

Sepsis/septic shock frequently occurred as a lethal complication in the intensive care unit. Endoplasmic reticulum stress (ERS) leading to the disturbance of cellular proteostasis played an important role in the sepsis-induced multiple organ dysfunction. Previous studies showed that several ERS molecule were involved in. It is not clear which ERS molecule could be competent as prognostic indicators of sepsis. Transcriptomic datasets containing gene expression profiles of sepsis patients and healthy controls were downloaded from the GEO database. Consensus clustering was performed to identify sepsis molecular subtypes associated with ERS. An integrated machine learning approach was conducted to screen potential prognostic markers for sepsis. The overactivated ERS-related sepsis subgroup were identified according to higher APACHE II scores and poor prognosis. Further molecular characterization and immune function analysis of this subgroup revealed that overactivated ERS-related sepsis was linked to excessive neutrophil extracellular trap (NET) formation, inflammatory response and pronounced immunosuppression. AHSP, FIS1, REXO2 and SYF2 were identified as key prognostic markers for this sepsis subtype. Their expressions following sepsis and their role in the severity of sepsis were validated by in vivo experiments. Furthermore, a prognostic risk model with the four genes was established as an independent and superior prognostic indicator, outperforming APACHE IV score and cardiovascular insufficiency in predicting outcome for septic patients. In summary, four ERS-related genes play an important role in sepsis-induced organ dysfunction, and the ERS-related prognostic model shows great potential as a major forewarning model.