Exogenous Cholera Toxin B Exacerbates Experimental Periodontal Bone Loss and is Associated with Serpinb3 K63-Lactylation and Macrophage Reprogramming

The cholera toxin B subunit (CTB), traditionally regarded as a non-toxic immunomodulator, has recently been implicated in epigenetic regulation; however, its role in periodontitis remains unclear. Here, we identify exogenous CTB aggravates experimental periodontal inflammation. In a murine model of periodontitis, CTB markedly exacerbated alveolar bone loss, suggesting its pathogenic relevance in vivo. Mechanistically, integrated transcriptomic, proteomic, lactylomic, and experimental analyses suggested that CTB-associated inflammatory responses involve metabolic remodeling and enhanced Serpinb3 K63-linked lactylation in macrophages. Functional studies using Serpinb3-deficient macrophages and mice further demonstrated that Serpinb3 contributes to CTB-induced inflammatory activation and periodontal bone loss. These findings identify an experimental role of CTB in potentiating periodontal inflammation and bone destruction and suggest that increased Serpinb3 K63-lactylation is associated with CTB-induced macrophage reprogramming. However, the site-specific functional requirement of Serpinb3 K63-lactylation remains to be determined. This work provides mechanistic insight into host–toxin interactions and identifies a potential immunometabolic regulatory axis that warrants further investigation in inflammatory bone loss.