The oral mucosal barrier, the primary entry point for essential substances (water, food, air), is crucial for oral and systemic health. Comprising a salivary gel layer, commensal microbiota, stratified epithelia, underlying connective tissues, and immunocompetent cells, this complex interface orchestrates selective defense against pathogens and physical and chemical factors while facilitating the absorption of nutrient and bioactive compound. Disruption of this barrier is associated with oral pathologies (e.g. periodontitis) and systemic dysfunction, including cardiovascular, neurodegenerative, and metabolic diseases, underscoring its significance as a key determinant of systemic health. Although the etiology is multifactorial, the precise mechanisms linking oral mucosal barrier disruption to distant organ dysfunction remain incompletely characterized. Consequently, elucidating the underlying molecular networks and cross-organ communication pathways is imperative for oral and systemic health maintenance, as well as development of novel therapeutic strategies target oral and systemic diseases. This review synthesizes recent advances in understanding the molecular architecture of the oral mucosal barrier, explores its local and systemic regulatory networks, and evaluates emerging innovations in barrier-targeted precision medicine approaches.
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