Integrated transcriptomic and functional analyses identify LAIR1 as a key immunoregulatory molecule in postoperative sepsis

Postoperative sepsis arises from a dysregulated host response to infection following surgical stress. Current non-specific biomarkers offer insufficient predictive value, highlighting the need to identify molecular signatures that may facilitate earlier recognition of postoperative sepsis while providing insight into the underlying immune regulatory mechanisms.

Transcriptomic datasets comprising postoperative septic and non-septic surgical cohorts, together with independent cohorts of sepsis and non-infectious systemic inflammation, were analyzed using Weighted Gene Co-expression Network Analysis and machine-learning approaches to identify hub genes. A diagnostic nomogram was constructed and validated across independent cohorts. A murine postoperative endotoxemia model (tibial fracture surgery followed by LPS challenge) was used for in vivo validation. Single-cell RNA sequencing analysis and LAIR1 antibody blockade were performed to assess cellular and functional relevance.

A four-gene signature comprising LAIR1, PLAC8, ACSS2, and PCOLCE2 was identified. The resulting model achieved AUCs of 0.865 in GSE131761, 0.965 in GSE74224, 0.827 in E-MTAB-1548, 0.929 in GSE65682, and 0.997 in GSE77167. Among the four genes, LAIR1 showed the most sustained upregulation in peripheral blood and multiple organs during postoperative endotoxemia. Single-cell analysis identified monocytes as the predominant circulating source of LAIR1. LAIR1 blockade increased systemic cytokine release, aggravated multiorgan injury, and reduced survival.

The four-gene signature reproducibly distinguished sepsis from infection-negative systemic inflammation across surgical and broader ICU cohorts. LAIR1 exhibited monocyte-enriched expression and a protective immunoregulatory role in postoperative endotoxemia, supporting its relevance to immune dysregulation of sepsis.