Downregulation of USP39 in sepsis reflects immune dysfunction and offers diagnostic and prognostic value

USP39 is involved in mRNA splicing and stress responses. This study analyzed USP39 expression and its clinical relevance in sepsis, aiming to provide a novel treatment target for sepsis.

The RNA-seq datasets were used for analyzing the expression profile and clinical significance of USP39 in both sepsis and control groups. Functional pathway enrichment was performed using GSEA and GSVA with the clusterProfiler package (3.14.3). Immune infiltration was evaluated via single-sample GSEA (ssGSEA). The prognostic value of USP39 was assessed utilizing Cox regression, and its diagnostic performance was determined via receiver operating characteristic (ROC) curve analysis employing the survival (3.5.7) and pROC (1.18.5) packages, respectively. For single-cell RNA-seq (scRNA-seq) data (GSE175453), we performed quality control, normalization, principal component analysis (PCA), batch correction, clustering, and Uniform Manifold Approximation and Projection (UMAP) visualization employing the Seurat 4.4.0 package. THP-1 cells were treated with lipopolysaccharide (LPS) to mimic septic injury. USP39 was overexpressed via pcDNA3.1 transfection. Cellular assays were conducted to measure cell viability, apoptosis, and inflammatory cytokines (IL-1β, IL-6, TNF-α).

Our study found that USP39 was significantly downregulated in sepsis patients and was associated with age, diabetes, and Intensive Care Unit (ICU)-acquired infections. Functional enrichment analysis revealed that high USP39 expression was linked to metabolic processes, primary immunodeficiency, and spliceosome, and immune response and inflammation pathway. In addition, USP39 also exhibited a high diagnostic value and was identified as an independent prognostic marker in sepsis. ssGSEA revealed higher infiltration of CD8⁺ T cells, activated B cells, and CD4⁺ T cells in the high USP39 expression group, while Th17 and NK cells were more abundant in the low USP39 expression group. According to the results of scRNA-seq analysis, USP39 exhibited significant differential expressions in monocytes and T cells, with low expression observed in sepsis. Furthermore, in vitro experiments confirmed that overexpression of USP39 significantly enhanced cell viability and suppressed apoptosis in LPS-induced THP-1 cells while also inhibiting the expression of inflammatory cytokines.

The significant downregulation of USP39 was correlated with both clinical features and immune infiltration in sepsis, highlighting its role in immune regulation and its potential as a prognostic biomarker.