To examine the role of the intracellular labile iron pool (LIP) in the induction of inflammatory responses, we investigated the anti-inflammatory effect of the iron chelator deferoxamine (DFO) on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophage cells and endotoxic shock in mice in the present study. Our data showed that DFO significantly decreased LPS-induced LIP and ROS upregulation. We then found that DFO inhibited phosphorylation of MAP kinases such as ERK and p38 and also inhibited the activation of NF-kappa B induced by LPS. Furthermore, the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), nitric oxide (NO) and prostaglandin E2 (PGE2) induced by LPS was inhibited by DFO in RAW264.7 macrophages. Administration of DFO significantly decreased the mortality and improved the survival of septic mice with lethal endotoxemia in LPS-injected mice. These results demonstrate that iron plays a pivotal role in the induction of inflammatory responses and against septic shock. DFO has effective inhibitory effect on the production of inflammatory mediators via suppressing activation of MAPKs and NF-kappa B signaling pathways; it also has a protective effect on LPS-induced endotoxic shock in mice. Our findings open doors to further studies directed at exploring a new class of drugs against septic shock or other inflammatory diseases by modulating cellular chelatable iron. (C) 2015 Elsevier Inc. All rights reserved.