Treating sepsis by targeting neutrophil extracellular traps: a systematic review and meta-analysis

Background Sepsis, a leading cause of death worldwide, is characterized by dysregulated host immune responses and multi-organ dysfunction. Neutrophil extracellular traps (NETs) are extracellular fibers from activated neutrophils that contribute to the immune response. However, excessive NETs formation during sepsis may exacerbate inflammation, thrombosis, and tissue injury, potentially affecting sepsis prognosis. We examined whether NETs-modulating interventions are beneficial in experimental sepsis models. Methods Following PRISMA guidelines, this review analyzed studies from PubMed and Scopus that reported NETs-targeting therapies and included outcome measures. A meta-analysis of random-effects models using a restricted maximum likelihood estimation was performed with a priori moderators including NETs quantification tier, intervention timing relative to insult, and intervention class. Results In 33 included studies, the therapies significantly reduced NETs levels, while three studies increased NETs following treatment. The a priori moderators, NETs tier and treatment timing, were not significant, whereas intervention class significantly modified treatment effects. The treated groups had a lower risk of death and reduced IL-6, IL-1β, TNF-ɑ levels when compared to the control group. The treatments reduced tissue injury with considerable heterogeneity (I 2 =68.4%) and should be cautiously interpreted due to small study numbers. NETs modulation was significantly associated with a decrease in cytokine concentration and tissue injury. The heterogeneity of protocols, diverse outcome measures, publication bias, and overall poor reporting quality of the studies warranted conservative effect estimates and cautious interpretation of findings. Conclusion Our meta-analysis suggests NETs modulation is associated with reduced mortality risk, attenuated organ injury, and decreased inflammation, based primarily on LPS endotoxemia rodent models. Notably, experimental protocols and model limitations impede the translatability of these therapies for clinical care at this stage of research. Trial registration In accordance with the guidelines, our systematic review protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO) registration number CRD420251124339 and was published with INPLASY on 20 August 2025