Single-cell transcriptomic landscape delineates pathogenic NK cell subpopulations and key mediators in systemic inflammatory response syndrome
Systemic inflammatory response syndrome (SIRS) carries high ICU morbidity, sepsis lacks standardized therapies, and stage-variable natural killer (NK) cell function in SIRS remains poorly defined due to insufficient single-cell evidence. Herein, we analyzed public LPS-induced SIRS peripheral blood single-cell RNA sequencing (scRNA-seq) data (GSE212092) via multiple bioinformatic algorithms to dissect NK heterogeneity, followed by in vitro functional verification using NK-92 cells with IGF1 stimulation or IGF1R knockdown. We identified distinct cell types and 6 distinct NK subpopulations (C0-C5). Pro-inflammatory C0 and proliferative C2 IGF1R⁺ expanded in early SIRS, whereas stemness-high C3-C5 accumulated during late immunosuppression. MHC-I and CCL5-CCR1 dominated NK-related intercellular crosstalk, and unique transcription regulatory modules existed across NK subpopulations. Functional assays verified IGF1/IGF1R signaling dose-dependently promotes NK inflammatory cytokine release, cytotoxic gene expression, cell viability and target cell killing. These findings delineate dynamic NK subpopulation remodeling during SIRS and validate IGF1/IGF1R as a potential key pathway governing NK effector function, providing a transcriptomic basis for identifying candidate biomarkers and potential therapeutic targets in SIRS.