Treponema pallidum lipoprotein Tp0768 promotes H3K18 Lactylation modification to target PTK2 and enhance endothelial permeability.

Syphilis is a systemic sexually transmitted disease, yet the mechanisms underlying the dissemination of its causative pathogen, Treponema pallidum (T.pallidum), within the host remain incompletely understood. Previous studies have shown that T.pallidum can damage vascular endothelial cells, thereby breaching the endothelial barrier to invade lymph nodes at the infection site. This facilitates its systemic dissemination via the bloodstream, leading to persistent infection across multiple vascular and tissue compartments. However, the precise molecular mechanisms governing this process remain elusive. In this study, we identified that the key pathogenic antigen Tp0768 of T.pallidum significantly enhances lactate secretion and global histone lactylation upon interaction with endothelial cells. Further investigations revealed a marked increase in histone H3 lysine 18 lactylation (H3K18la) in response to Tp0768 exposure. We demonstrated that elevated H3K18la enhances the accessibility of the PTK2 promoter, thereby directly upregulating PTK2 expression. This, in turn, leads to the downregulation of the tight junction proteins ZO-1 and occluding, ultimately increasing endothelial permeability. Collectively, our in vitro findings identify the H3K18la-PTK2 axis as a novel epigenetic-metabolic pathway through which Tp0768 may compromise endothelial barrier integrity. These results provide a potential molecular framework for understanding T.pallidum dissemination, highlighting a target for future investigation into therapeutic strategies against syphilitic vascular injury.