Abstract Cigarette smoke is a major risk factor for chronic respiratory diseases, yet the molecular mechanisms underlying its effects on pulmonary defense remain incompletely understood. While transporters such as P-glycoprotein and CFTR have been implicated in smoking-related dysfunction, little is known about the impact of cigarette smoke on peptide transporter 2 (PEPT2), which plays a dual role in xenobiotic disposition and host defense by mediating the uptake of di- and tripeptides, bacterial fragments, and peptide-like drugs. Here, we investigated the effects of cigarette smoke extract (CSE) on the functional expression of PEPT2 in alveolar epithelial cells. Using the human H441 cell line, we found that CSE reduced PEPT2 activity and mRNA expression in a concentration-dependent manner. Among signaling inhibitors, only PD98059 reversed the CSE-induced suppression, whereas U0126 had no effect. Consistently, the AhR ligand benzoapyrene decreased PEPT2 expression and function, and this effect was abolished by AhR antagonists. Other AhR ligands, including leflunomide and omeprazole, produced similar inhibitory effects. These findings indicate that CSE suppresses PEPT2 in an AhR-dependent manner, while the underlying transcriptional mechanisms remain to be clarified. These findings suggest that PEPT2 is a previously unrecognized target of cigarette smoke–related transporter regulation and are consistent with the involvement of AhR signaling in its suppression. These findings provide insight into potential alterations in epithelial transport function and their possible implications for pulmonary defense and drug disposition in smokers.
Kawami et al. (2026) studied this question.