Rigosertib inhibits MEK1–ERK pathway and alleviates lipopolysaccharide‐induced sepsis

BACKGROUND: Here, by using the lipopolysaccharide (LPS)‐induced mice sepsis model, we treated septic wild‐type (WT) mice or MEK1(DD) mice with rigosertib to evaluate its prospective effects on sepsis. METHODS: We also generated macrophages derived from bone marrow from WT or MEK1(DD) mice. These macrophages were pretreated with rigosertib and then induced with LPS or poly I:C. RESULTS: Rigosertib suppressed LPS or poly I:C‐induced expression of inflammatory cytokines (tumor necrosis factor‐alpha [TNF‐α] and interleukin‐6 [IL‐6], and IL‐23) in WT bone marrow–derived macrophages while failed to affect the upregulation of TNF‐α and IL‐6 in LPS‐treated bone marrow–derived macrophages from MEK1(DD) mice. Rigosertib promoted survival rate, ameliorated lung injury, and reduced inflammatory cytokine levels in serum of WT septic mice. CONCLUSION: In contrast, the effects of rigosertib on sepsis were abrogated in septic MEK1(DD) mice, which had inducible constitutive activation of MEK1 signaling. Rigosertib alleviated LPS‐induced sepsis inhibits MEK1/ERK signaling pathway.