Excessive inflammation plays a detrimental role in endotoxemia. A recent study indicated that alarmins such as high mobility group box I (HMGB1) have drawn attention as therapeutic targets of sepsis. Post translational modification (i.e., acetylation of lysine residues) of HMGB1 leads to the release of HMGBI into the cellular space, operating as a warning signal that induces inflammation. Sirtuin 1 (SIRTI) has been shown to negatively regulate HMGBI hyperacetylation and its extracellular release in sepsis. Therefore, we hypothesized that the S-nitrosylation (SNO) of SIRTI may disrupt the ability of SIRTI to negatively regulate the hyperacetylation of HMGBI. As long as the S-nitrosylation of SIRTI occurs during septic conditions, it may worsen the situation. We found that the activity of SIRT1 decreased as the SNOSIRT1 levels increased, resulting in HMGBI release by LPS in RAW264.7 cells. Both the iNOS inhibitor (1400 W) and silencing iNOS significantly inhibited SNO-SIRTI, allowing increases in SIRTI activity that decreased the HMGBI release by LPS. SNAP, a NO donor, significantly increased both SNO-SIRTI levels and the HMGBI release that was accompanied by decreased sirti activity. However, sirtinol, a Sirtl inhibitor, by itself decreased Sirtl activity compared to that of the control, so that it did not affect already increased SNO-SIRT levels by SNAP. Most importantly, in lung tissues of LPS-endotoxic mice, significantly increased levels of SNO-SIRT were found, which was inhibited by 1400 W treatment. Plasma nitrite and HMGB1 levels were significantly higher than those in the sham controls, and the elevated levels were significantly lowered in the presence of 1400 W. We concluded that the S-nitrosylation of Sirtl under endotoxic conditions may uninhibit the acetylation of HMGB1 and its extracellular release. (C) 2018 Elsevier Inc. All rights reserved.