Melatonin attenuates peri-implantitis by promoting HAT1-mediated succinylation of p65 to inhibit p65 nuclear translocation.

Peri-implantitis is caused by bacterial infection. Melatonin (Mel) is effective on treating periodontitis, but its efficacy on peri-implantitis remains unclear. The present study assessed the therapeutic effects of Mel on peri-implantitis and its mode of action. Peri-implant in vivo model was generated by implanting titanium implants and feeding rats with sugar water. Human periodontal ligament stem cells (hPDLSCs) were treated with lipopolysaccharide (LPS) to induce inflammation in vitro. Inflammation was evaluated by measuring cytokines contents. Osteogenic differentiation was assessed by Alkaline phosphatase and Alizarin red S staining, and measurements of RUNX2, OCN and OPN through quantitative real-time PCR. Effect of Mel in vivo was evaluated by hematoxylin-eosin staining. Results showed that Mel significantly inhibited inflammation but facilitated osteogenic differentiation in LPS-induced hPDLSCs. In LPS-treated hPDLSCs, Mel enhanced protein succinylation while elevating HAT1 expression. Notably, the beneficial effects of Mel on suppressing inflammation and promoting osteogenic differentiation were reversed by HAT1 knockdown. Mechanically, HAT1 knockdown inhibited succinylation and stability of p65 protein, but enhanced phosphorylation of p65 and p65 nuclear translocation at K311 site. Consistently, in the rat peri-implantitis model, Mel treatment suppressed inflammatory infiltration and promoted osteogenic differentiation, effects which were dependent on HAT1 expression and associated with increased p65 succinylation and decreased phosphorylation. In conclusion, we demonstrated that Mel exerts therapeutic effects on peri-implantitis in vivo, and our in vitro data suggests this may be mediated by promoting p65 succinylation by upregulating HAT1, thereby inhibiting p65 nuclear translocation.