Systemic administration of Smaducin-6 showed a significant therapeutic effect on mouse TLR4-mediated inflammatory disease models, cecal-ligation–puncture (CLP)-induced sepsis, and lipopolysaccharide-induced endotoxemia, by inhibiting pro-inflammatory cytokine production and apoptosis while enhancing neutrophil migration and bacterial clearance. Here, TLR4 is linked to serum lipopolysaccharide activity.