Systematic review proposes S100A8/A9–NETosis feedback loop as core sepsis mechanism.

This is a systematic review that provides a narrative synthesis of the proposed S100A8/A9–NETosis feedback loop as a core pathological mechanism in sepsis. The authors systematically propose this loop and explore its potential pathways, concluding it drives neutrophil-mediated hyperinflammation, monocyte/macrophage polarization, immune paralysis, and immune thrombosis, while contributing to organ-specific injury.

The review does not report pooled effect sizes, trial-level data, or specific study populations, as these are not provided in the abstract. The authors note key limitations, including that few studies have integrated S100A8/A9 and NETosis into a unified feedback loop, and that a systematic description of this loop in myeloid cell–platelet interactions and organ damage has not been established.

Practice relevance is framed as providing new perspectives for sepsis treatment through potential therapeutic strategies targeting the loop, but the review does not establish causation from primary trials. The authors caution against inferring specific therapeutic efficacy or claiming causation beyond the proposed mechanistic loop. This synthesis is based on existing evidence and should be interpreted as a hypothesis-generating framework rather than a guide for clinical practice.