High mobility group box 1 (
HMGB1), a
cytokine present in the late phase of
sepsis, may be a potential target for the treatment of
sepsis. For
HMGB1 to be actively secreted from macrophages during
infections, it must be post-translationally modified. Although
ethyl pyruvate (EP), a simple aliphatic
ester derived from
pyruvic acid, has been shown to inhibit the release of
HMGB1 in
lipopolysaccharide (LPS)-treated RAW 264.7 cells, the underlying mechanism(s) are not yet clear. We investigated the hypothesis that the upregulation of
SIRT1 by EP might promote the deacetylation of
HMGB1, which reduces
HMGB1 release in LPS-activated macrophages. Our results show that EP induced the expression of the
SIRT1 protein in RAW264.7 cells and that it significantly inhibited the LPS-induced acetylation of
HMGB1. Transfection with a SIRT1-overexpressing vector resulted in a significant decrease in the acetylation of
HMGB1 in LPS-activated RAW264.7 cells relative to control cells. The genetic ablation or the pharmacological inhibition of
SIRT1 by
sirtinol increased LPS-induced
HMGB1 acetylation. Moreover, EP inhibited the acetylation of
HMGB1 in peritoneal macrophages treated with LPS. Interestingly, EP significantly reduced the LPS-induced phosphorylation of STAT1, which was significantly reversed by siSIRT1 transfection in RAW264.7 cells, indicating that
SIRT1 negatively regulates the phosphorylation of STAT1. Overall, the results show that EP promotes the deacetylation of
HMGB1 via the inhibition of STAT1 phosphorylation through the upregulation of
SIRT1, which reduces
HMGB1 release in LPS-activated RAW264.7 cells. In conclusion, EP might be useful in the treatment of diseases that target
HMGB1, such as
sepsis.