Erastin Inhibits Septic Shock and Inflammatory Gene Expression via Suppression of the NF-κB Pathway

Abstract

Sepsis is a life-threatening condition that is caused by an abnormal immune response to infection and can lead to tissue damage, organ failure, and death. Erastin is a small molecule capable of initiating ferroptotic cell death in cancer cells. However, the function of erastin in the inflammatory response during sepsis remains unknown. Here, we showed that erastin ameliorates septic shock induced by cecal ligation and puncture or lipopolysaccharides (LPS) in mice, which was associated with a reduced production of inflammatory mediators such as nitric oxide, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Pretreatment with erastin in bone marrow-derived macrophages (BMDMs) significantly attenuated the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, and IL-1β mRNA in response to LPS treatment. Furthermore, we also showed that erastin suppresses phosphorylation of IκB kinase β, phosphorylation and degradation of IκBα, and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in LPS-stimulated BMDMs. Our findings suggest that erastin attenuates the inflammatory response by suppressing the NF-κB signaling pathway, resulting in inhibition of sepsis development. This study provides new insights regarding the potential therapeutic properties of erastin in sepsis.

Protective Effects of Smilax glabra Roxb. Against Lead-Induced Renal Oxidative Stress, Inflammation and Apoptosis in Weaning Rats and HEK-293 Cells

“…Next, HEK-293 cells were cultivated with a Cy3-conjugated secondary antibody for 1 h. Finally, cells were cultivated with DAPI for 5 min. Pink fluorescence (red and blue images overlaid) indicated nuclear translocation of NF-κB p65 protein, and could be observed simultaneously by a confocal laser scanning microscope (Zeiss, Wetzlar, Germany) at an excitation wavelength of 350 nm and 540 nm for DAPI and Cy3 ( Oh et al., 2019 ).…”

Posttranslational Modifications in Ferroptosis

“…The Toll-like receptor 4- (TLR4-) nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κ B) signaling pathway activates the expression of several proinflammatory cytokine genes that play pivotal roles in inflammatory disorders, such as sepsis, ulcerative colitis, myocardial infarction, and I/R injury [ 78 – 80 ]. The pretreatment of bone marrow-derived macrophages (BMDMs) with the ferroptosis inducer erastin significantly attenuates the expression of proinflammatory cytokines (e.g., inducible nitric oxide synthase, tumor necrosis factor- (TNF-) α , and interleukin- (IL-) 1 β ) induced by lipopolysaccharide (LPS) treatment, and these effects are mediated by inhibition of the phosphorylation of I κ B kinase β (IKK β ) and the phosphorylation and degradation of I κ B α and NF- κ B and thereby lead to the suppression of sepsis development [ 80 ]. Ferroptosis is detected in intestinal epithelial cells from patients with ulcerative colitis and mice with colitis, and Fer-1 alleviates experimental colitis [ 79 ].…”

Global Research Trends of Ferroptosis: A Rapidly Evolving Field With Enormous Potential

“… Li et al (2018) demonstrated that Gpx4 activator can suppress inflammatory conditions through the inhibition of the NF-κB pathway. And other researchers also discovered that erastin had similar roles in inflammatory response by suppressing the NF-κB signaling pathway, resulting in inhibition of sepsis development ( Oh et al, 2019 ).…”