To extend our understanding of previous studies on the pathogenesis and mechanism of high mobility group box 1 (HMGB1) in chronic rhinosinusitis with nasal polyps (CRSwNP), here we show that Sirtuin 6 (Sirt6), one of the Sirtuin family members which are widely studied in aging, DNA repair, metabolism, inflammation and cancer, was expressed in normal nasal mucosa using immunohistochemical staining and Western blot assay. Sirt6 expression levels were decreased in CRSwNP tissue. Sirt6 expression levels were modulated by small interfering RNA transfection in human nasal epithelial cells (HNE). We found that depletion of Sirt6 suppressed the number of human nasal epithelial cell cilia, and dramatically induced HMGB1 translocation from nucleus to cytoplasm in the HNE cells. Glycyrrhizic acid (GA) and glycyrrhetinic acid (GTA) are specific chemical compounds that may be isolated from the licorice plant. GTA has been shown to have anti-inflammatory and anti-allergic activity: it binds selectively to HMGB1 protein released extra-cellularly and inhibits its cytokine activities through a scavenger mechanism on the protein accumulation. In an in vitro study we used the 18-β-stereoisomer of GTA to enhance Sirt6 expression levels, inhibiting through this mechanism the translocation of HMGB1 protein from nucleus and reversing its extracellular accumulation stimulated by lipopolysaccharides. These findings reveal a previously unknown role for nasal mucosa steady-state conditions in the control of Sirt6 activity, and provide evidence for a relationship between HMGB1 and Sirt6 in CRSwNP, and promising benefits of glycyrrhetinic acid for CRSwNP patients.