Epithelial IL-6 trans-signaling (IL-6TS) activation in the absence of type 2 airway inflammation has been defined a novel phenotype of asthmatics and may drive airway epithelial dysfunction, including reduced epithelial integrity and induction of gene signatures associated with airway remodeling via STAT3. This study investigated the implication role of SERPIN B3/B4 in IL-6TS mediated fibrogenesis and epithelial disruption in asthmatics. Our study demonstrated that the protein and mRNA expression of SERPIN B3/B4 were up-regulated in the bronchial epithelium of severe T2 and non-T2 asthmatics. The sIL-6R levels were elevated in the serum of those severe asthmatics, and the sIL-6R levels decreased after asthma was under control. IL-6TS directly induced SERPIN B3/B4 mRNA and protein expression, and subsequently TGF?1, CTGF, fibronectin, Collagen I and V protein expression through STAT3 in primary airway epithelial cells from asthmatics. IL-6TS also induced epithelial cells decreasing junctional protein, E-cadherin expression and TEER leading to an increased para-cellular flux of dextran. Use sgp130 or SERPIN B3/B4 siRNA suppressed IL-6TS induced fibrogenic proteins synthesis, E-cadherin loss and increased epithelial permeability. In animal study, epithelial expression of SERPIN B3 was up-regulated in HDM challenged model, and sgp130 pretreatment reduced SERPIN B3/B4 expression and E-cadherin loss. Thus, IL-6TS is implicated in bronchial epithelial SERPIN B3/B4 mediated fibrogenesis and epithelial disruption in severe asthma. IL-6TS casts a role in airway dysfunction in terms of airway remodeling and epithelial disruption through SERPIN B3/B4.