This study aimed to characterize the MUC1-RBFOX3-CLDN1 degradation system in AR pathogenesis.As in normal human lung tissue, CLDN1 has been observed to be highly expressed in RBFOX3- pos. cells; the similar phenotype was evaluated in the nasal mucosa tissue of AR patients, and nasal epithelial cells labeling ubiquitin with RBFOX3 deficiency were observed in AR patients.Furthermore, CLDN1 expression and RBFOX3 expression were significantly downregulated in the nasal mucosa of AR patients.Taken together, these results suggest that CLDN1 ubiquitination regulated by RBFOX3 may be involved in MUC1-mediated AR pathogenesis.After establishing the AR mice model with the ubiquitin-proteasome inhibitor MG132 nasal administration, CLDN1 and RBFOX3 were observed to be depressed in the nasal mucosal tissue of AR mice, which is deteriorated in MUC1 deficiency.CLDN1 and RBFOX3 were observed to be depressed in the nasal mucosal tissue of AR mice, which is deteriorated in MUC1 deficiency.These findings suggest that MUC1-mediated ubiquitin-dependent CLDN1 degradation could be involved in AR pathogenesis.Immunoblots showed that RBFOX3 expression level was depressed in MUC1 cells and CLDN1 expression level was significantly decreased in MUC1 cells and RBFOX3 cells.Therefore, we hypothesized that IL-4 stress generated upon CLDN1 depression could be the result of MUC1- mediated defect in the expression of RBFOX3.Nano LC-MS/MS anal. revealed two E3 ubiquitin ligase interacted with CLDN1 directly: Smurf2 and MARCH5 (Figure S4B).This study only investigated elevated levels of MARCH5 in simulated epithelial cells (Figure S4C), while the expression differences of Smurf2 and MARCH5 in AR mice were not monitored (Figure S4D).In conclusion, this study demonstrates MUC1 deficiency inhibits CLDN1 expression via RBFOX3 shortage augment ubiquitin-proteasomal degradation in AR.