Mechanical Pressure, Histone Lactylation, And Salivary Gland Fibrosis

To investigate the link between mechanical pressure and histone lactylation in salivary gland fibrosis. An animal model of salivary gland fibrosis was constructed by anatomically isolating and ligating the submandibular gland ducts of mice. An in vitro model of obstructive submandibular gland fibrosis was established using a cell pressurization method in mouse embryonic fibroblasts (NIH-3T3). Post-ligation murine submandibular gland tissue sections demonstrated pronounced collagen deposition within the stromal compartment, suggesting the role of pressure-responsive signaling pathways. YAP Signaling - a central mediator of mechanotransduction - was activated in fibroblast under mechanical pressure. Interestingly, mechanical pressure also increases the level of LDHA, LDHB, and Histone H3K18 lactylation (H3K18la), suggesting the link between Mechanical pressure and Histone lactylation. Pharmacological inhibitor of YAP resulted in downregulation of COL1 and H3K18la levels. Oxamate, a selective LDHA inhibitor, was employed to evaluate the functional consequences of lactylation suppression on fibrotic pathways, which downregulates H3K18la and inhibits the expression of THBS1, an activator of latent TGF-β. In vivo experiments verifies the role of YAP and LDHA inhibitor in alleviating salivary gland fibrosis and hyposalivation. This study highlights the link among mechanical pressure, histone lactylation, and salivary gland fibrosis. Our results indicate a potential therapeutic strategy for tissue fibrosis.