Bulk peripheral-blood transcriptomic analysis identifies a STAT3/ARG1-associated myeloid immunosuppressive signature...

Sepsis involves immune dysregulation with myeloid activation and impaired antigen presentation. This study identified a compact immunosuppressive transcriptional signature associated with signal transducer and activator of transcription 3 (STAT3) and arginase 1 (ARG1) using public peripheral-blood transcriptomic datasets. GSE28750, including 10 sepsis samples and 20 healthy controls, was used for discovery; GSE65682, including 120 sepsis-related baseline/ICU-admission samples and 40 healthy controls, was used for external validation. Differential expression, enrichment, ssGSEA, and correlation analyses were performed in GSE28750, whereas candidate-gene directionality and composite-signature performance were reproduced in GSE65682. Differential expression analysis identified 482 genes, with 301 upregulated and 181 downregulated. Representative STAT3/ARG1-associated myeloid and immunoregulatory genes were upregulated, whereas HLA-DRA and HLA-DRB1 were downregulated. Enrichment analysis highlighted myeloid activation, IL6-JAK-STAT3 signaling, arginine metabolism, and impaired antigen processing and presentation. Sepsis samples had higher myeloid-derived suppressor cell (MDSC)-like scores than controls (0.72 ± 0.21 vs. -0.36 ± 0.18, P = 1.1 × 10 - 7). The composite signature showed exploratory diagnostic performance, with area under the receiver operating characteristic curve (AUC) values of 0.94 and 0.88 in the discovery and validation cohorts, respectively. This study provides a reproducible bioinformatic framework and candidate transcriptional signature for assessing sepsis-related myeloid immunosuppressive remodeling.

The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05087-1.