Esculetin,a natural derivative from the traditional and widely-used Chinese medicinal herb Cortex Fraxini,has a vari-ety of pharmacological effects,especially in anti-inflammation.However,it is not clear whether esculetin has a therapeutic effect on sepsis.This study aimed to investigate the anti-inflammatory and protective effects of esculetin on early sepsis.The results showed that the lung injury was significantly relieved with the treatment of esculetin,accompanied with the restrained production of inflammatory factors including IL-1β,IL-6,TNF-α,CCL2 and iNOS during the early phase of E.coli-induced sepsis.Of note,activation of NF-κB and STAT1/STAT3 signals,the main upstream signals of many inflammatory factors,were attenuated by esculetin in both lung tissues from septic mice and LPS-stimulated macrophage.These findings suggested that the protection of esculetin against early sepsis should be related to its anti-inflammatory effect,which was at least partly due to its inhibition on NF-κB and STAT1/STAT3 signaling path-way in macrophage.Thus,esculetin could serve as a potential therapeutic agent by rebalancing innate immune response in macro-phage for the treatment of early sepsis.