Establishment and validation of a rat sepsis model aligned with sepsis-3 via Staphylococcus aureus tail vein infection.

Sepsis, a life-threatening organ dysfunction stemming from uncontrolled host responses to infection, continues to be a leading global health threat. Despite the establishment of diverse preclinical animal models for sepsis research, their inherent deficiencies have significantly hindered their clinical translation. In this study, we developed a rat model of sepsis through continuous tail vein injection of a single, defined Staphylococcus aureus strain. Bacteriological identification confirmed the exclusive presence of the inoculated pathogen. The model recapitulated key clinical features of human sepsis, including altered mental status, respiration, and fever. Biochemical tests of peripheral blood revealed that the model rats and clinical sepsis patients presented similar alterations in indicators related to coagulation function and the cardiac, hepatic, and renal systems. Compared with the control group, model rats exhibited increased platelet counts (P < 0.05), total bilirubin, urea, and cystatin levels (P < 0.001, P < 0.01, P < 0.05, respectively). Histopathological and ultrastructural examinations confirmed multi-organ damage. Additionally, tandem mass tag proteomics analysis identified a total of 707 significantly differentially expressed proteins (P < 0.05, fold change > 1.2), with 279 upregulated and 428 downregulated in the model group compared to the control group. These proteins were enriched in inflammatory and immune responses, signal transduction, and oxidative stress pathways, systematically revealing molecular-level dysregulation. Collectively, our model meets Sepsis-3 and provides a standardized, stable, and reproducible platform for mechanistic research and therapeutic development. KEY POINTS: A standardized rat sepsis model via sustained Staphylococcus aureus tail vein injection was established. The model meets Sepsis-3 through multilevel clinical and pathological validation. It provides a stable, reproducible tool for mechanistic research and therapeutic development.