Heated tobacco product-derived aerosol extract impairs gingival epithelial barrier function via CXADR downregulation

In our previous study, coxsackievirus and adenovirus receptor (CXADR), a tight junction-associated protein, was shown to play a critical role in maintaining gingival epithelial barrier function. Smoking is a well-established risk factor for periodontal disease; however, the effects of heated tobacco products on epithelial barrier function remain poorly understood. The present study investigated the effects of three heated tobacco product extracts (HTPE) on CXADR expression in human gingival epithelial cells. Exposure to the three HTPE significantly reduced CXADR expression, and functional analyses supported the involvement of nuclear factor erythroid 2-like 1 (NFE2L1), a CNC-bZIP transcription factor, in the three HTPE-induced CXADR downregulation in gingival epithelial cells. In a three-dimensional multilayered gingival epithelial tissue model, HTPE exposure increased permeability to 40 kDa dextran and lipopolysaccharide, whereas CXADR overexpression attenuated the three HTPE-induced increase in permeability to these substrates. These findings indicate that the three HTPE compromise gingival barrier integrity, with CXADR downregulation contributing to increased permeability to bacterial components.