Elabela mitigates the early stage of inflammation in sepsis by inhibiting pyroptosis.

ABSTRACT

OBJECTIVES: This study aims to investigate the potential therapeutic role of Elabela (ELA) in mitigating the sepsis-induced inflammatory storm, a phenomenon commonly associated with multiple organ dysfunction syndrome (MODS) and increased mortality. Our findings show the pathogenesis of sepsis, identifying ELA as a promising therapeutic target. METHODS: We conducted a comprehensive analysis of electronic medical records and blood samples from septic patients to assess the incidence of severe organ complication and characterize the inflammatory response. Subsequently, we measured the expression levels of ELA and various inflammatory factors in serum, and performed correlation analysis to explore the relationship between them, aiming to identify the cells and inflammatory pathways targeted by ELA. Furthermore, animal and cellular experiments were conducted to investigate the molecular mechanism underlying the therapeutic effect of ELA. RESULTS: Our findings revealed a higher prevalence of severe organ complications among septic patients, contributing to adverse prognoses and increased mortality. Notably, these patients exhibited significantly elevated levels of inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in their sera, indicating a robust inflammatory response. Correlation analysis revealed a negative correlation between ELA and IL-1ß in septic patients. Through animal and cellular experiments, we demonstrated that ELA inhibits the cleavage of caspase-1 and gasdermin D (GSDMD), thereby attenuating pyroptosis and the inflammatory response. CONCLUSIONS: ELA is a promising therapeutic agent for mitigating the deleterious effects of sepsis. Its ability to inhibit macrophage pyroptosis and suppress the inflammatory response offers a novel approach.