Oral epithelial barrier: Gatekeeper of mucosal immunity and driver of disease

The oral mucosal epithelium functions not only as a physical barrier but also as a dynamic immunomodulatory interface at the boundary between the oral environment and the host. It actively maintains host-microbial homeostasis and orchestrates mucosal immunity. Disruption of this intricate barrier is a hallmark of various oral inflammatory diseases, underscoring its pivotal role in pathogenesis. This review synthesizes recent advances demonstrating how the epithelium, as a central component of the mucosal immune community, contributes to health and disease through mechanisms including barrier integrity, pathogen recognition, antigen presentation, and crosstalk with immune cells. We further explore the dysregulation of epithelial homeostasis-including perturbed differentiation, compromised barrier function, and defective repair-which drives a self-sustaining cycle of inflammation and tissue damage. Moreover, emerging evidence from single-cell transcriptomics has revealed a novel epithelial function, termed inflammatory memory, whereby epithelial stem and progenitor cells retain lasting imprints of prior inflammatory encounters. This concept provides new insight into the chronicity of conditions such as periodontitis. By integrating these perspectives, we highlight the translational potential of targeting epithelial barrier pathways and leveraging epigenetic reprogramming underlying inflammatory memory, thereby informing precision strategies for the treatment of oral mucosal diseases.