SIRT6 activator MDL-800 alleviates periodontal inflammation by inhibiting AIM2 pathway

Periodontitis is an infectious and inflammatory disease. The inability to control clinical inflammation significantly contributes to unsuccessful periodontal treatment. As a key regulator of epigenetics, Sirtuin 6 is one of the NAD⁺-dependent histone deacetylase family members and has recently gained considerable interest in the context of inflammation. While MDL-800 has been demonstrated as an activator of SIRT6, its function in treating periodontitis remains unknown. In this study, animal experiments revealed that MDL-800 reduced alveolar bone resorption in ligature-induced periodontitis, particularly via reducing inflammation and inhibiting osteoclast production in a SIRT6-dependent manner. Furthermore, human gingival fibroblasts (HGFs) were exposed to lipopolysaccharide (LPS) to mimic periodontal inflammation in vitro. We noted that MDL-800 remarkably reduced expressions of pro-inflammatory cytokines in LPS-induced HGFs, which was neutralized by inhibiting SIRT6. Besides, MDL-800 could also reduce oxidative stress damage under inflammatory conditions. The suppression of AIM2 inflammasome activation was associated with the significant anti-inflammatory properties of MDL-800, as demonstrated by RNA sequencing and validation experiments. In conclusion, these findings suggest that MDL-800 was effective in reducing periodontal inflammation, partly by inhibiting AIM2 pathway in a SIRT6-dependent manner, demonstrating significant promise for enhancing therapeutic outcomes in periodontitis.