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Objectives and questions: Hemorrhagic shock (HS) in trauma patients remains a leading cause of preventable mortality worldwide and represents a critical challenge in acute care management. It results from rapid, significant blood loss that compromises tissue perfusion, oxygen delivery, and, ultimately, cellular function. Early recognition, prompt resuscitation, and coordinated multidisciplinary intervention are essential to improve survival outcomes and reduce secondary complications. Our study aimed to explore key biomarkers of ferroptosis following HS and validate their predictive value through bioinformatic analysis and animal experiments.

Material and methods: We compared the gene expression profiles between the control group (n=5) and the HS and resuscitation (HS/R) group (n=4) in the GSE26696 dataset, performing Differential Gene Expression (DGE) analysis to obtain differentially expressed genes (DEGs). Then, Protein-Protein Interaction (PPI) networks were constructed, and the top ten HUBgenes were screened from upregulated and downregulated DEGs, respectively. Gene Ontology (GO) and WikiPathways enrichment analyses were performed on HUBgenes to reveal their biofunctions. Gene Set Enrichment Analysis (GSEA) was applied to assess the enrichment of ferroptosis-related genes (FRGs) in the HS/R group, with their functions and related pathways being analyzed as well. Finally, a mice HS/R model was constructed, and the protein expression level of the key biomarker was verified by immunohistochemical staining of liver tissue.

Results: Our analysis identified multiple DEGs, among which IL-6 was the most significantly upregulated HUBgene in the HS/R group. GSEA showed that the FRGs, including markers, drivers, and suppressors, were all significantly enriched in the HS/R group, and IL-6 was again identified as the core pivoted driver gene of ferroptosis. Functional enrichment analyses suggested that these genes were mainly enriched in pathways such as inflammation, cell death, and so on. Lastly, animal experiments validated that, compared with the Control group, the protein expression level of IL-6 in the liver tissue of mice in the HS/R group was significantly increased, consistent with the results of bioinformatic analysis.

Discussion and conclusions: In conclusion, IL-6 expression is significantly upregulated after HS and is closely related to the ferroptosis process, indicating that IL-6 has the potential to serve as a biomarker for predicting ferroptosis in HS, providing a new direction for understanding its pathological mechanisms and developing new treatment strategies.