Sepsis-induced multiple organ dysfunction and inflammatory response are life-threatening symptoms without effective treatment.Fisetin,a dietary flavonoid extracted from berries and family Fabaceae,has displayed neuroprotective and anti-oxidant activities.In this study we investigated whether fisetin exerted a protective effect against sepsis-induced multiple organ dysfunction in mouse cecum ligation and puncture (CLP) model.The mice were injected with fisetin (10 mg/kg,ip) 0.5 h prior to CLP,and sacrificed 18 h after CLP.We found that fisetin administration significantly alleviated CLP-induced lung,liver and kidney injury,as well as the expression levels of interleukin (IL)-6,tumor necrosis factor (TNF)-α and IL-1β in bronchoalveolar lavage fluid (BALF).In lipopolysaccharide (LPS)-treated mouse bone marrow-derived macrophages (BMDMs),application of fisetin (3-10 μM) dose-dependently inhibited the expression levels of IL-6,TNF-α,IL-1β,and inducible nitric oxide synthase (iNOS).Furthermore,fisetin dose-dependently inhibited the phosphorylation of p38 MAPK,MK2,and transforming growth factor-β-activated kinase (TAK) 1 via attenuating the interaction between TAK1 and TAK-binding proteins (TAB) 1.These results demonstrate that fisetin is a promising agent for protecting against sepsis-induced inflammatory response and organ injury via inhibiting macrophage activation.