KDM6B/Pdk1 glycolytic pathway-driven ZEB2 lactylation promotes cellular cementum formation

Periodontitis is a common chronic inflammatory disease that ultimately results in irreversible tooth loss. Cementum, a bone-like tissue surrounding tooth roots, deteriorates as periodontitis advances, ultimately causing tooth loss. Therefore, cementum regeneration is considered a key factor in periodontal regeneration. Given the shared gene expression patterns and characteristics between cementum and bone, strategies for cementum regeneration may inform approaches for bone regeneration. Cementoblasts are responsible for cementum formation. This study identified lysine demethylase 6B (KDM6B) as a positive regulatory molecule that promotes cementoblast mineralization and formation. The seahorse assay revealed that KDM6B regulates glycometabolic reprogramming during cementoblast mineralization. Chromatin Immunoprecipitation (ChIP) sequencing and bulk RNA sequencing revealed that pyruvate dehydrogenase kinase 1 (PDK1), a crucial enzyme in glycolysis, is a direct target of KDM6B. Activation of the KDM6B-Pdk1 axis enhanced lactate production, driving lactylation of zinc finger E-box binding homeobox 2 (ZEB2). ZEB2 lactylation subsequently promotes cementoblast mineralization. Moreover, both in vitro and in vivo experiments showed that sodium lactate supplementation restores mineralization impaired by KDM6B suppression. In conclusion, our findings identify the KDM6B-Pdk1-ZEB2 lactylation axis as essential for cementogenesis, providing new insights for periodontal regeneration strategies.