PRC1 impairs sepsis host defense by suppressing NF-κB/JAK-STAT signaling and macrophage glycolytic reprogramming.

Sepsis is a life-threatening syndrome characterized by immune paralysis and impaired host defense. Effective macrophage-mediated bacterial clearance depends on tightly coordinated inflammatory signal transduction and infection-driven metabolic reprogramming toward glycolysis, yet the key molecular checkpoints governing this immunometabolic network remain poorly defined. Here, integrative transcriptomic analyses were performed to identify prognostic biomarkers in sepsis, leading to the recognition of Protein Regulator of Cytokinesis 1 (PRC1) as a core candidate associated with poor survival and an immunosuppressive phenotype. Functional and mechanistic studies using Escherichia coli-infected macrophages and a cecal ligation and puncture (CLP) murine model demonstrated that PRC1 acts as a negative regulator of macrophage innate immunity. PRC1 overexpression was associated with dampened NF-κB and JAK-STAT signaling, reduced phagocytic and bactericidal capacity, and attenuation of infection-induced glycolytic reprogramming together with relative preservation of mitochondrial metabolic features, whereas PRC1 silencing showed the opposite pattern. Consistently, PRC1 expression was elevated in septic mice, and PRC1 silencing reduced organ injury and bacterial burden and significantly improved survival. Collectively, these results support the interpretation that PRC1 is associated with altered macrophage immune-metabolic responses and may contribute to sepsis-associated immune dysfunction. PRC1 may therefore represent a potential target for future investigation aimed at restoring host defense in sepsis.