**5. Conclusions**

Although NF-κB signaling is a well-characterized pathway in airway inflammation, we, for the first time, show activation of Bcl10-mediated NF-κB pathway in severe asthmatic fibroblasts. Furthermore, Bcl10 immunoreactivity in the subepithelium of airway tissues varied in intensity and distribution with increasing severity of asthma, relaying its importance in asthma severity. We further identified Bcl10 as a mediator of signal transduction from TLR4 to the activation of NF-κB inducible genes, including of IL-6, IL-8 and TGF-β1, in bronchial fibroblasts. This allows us to selectively target Bcl10 to impede its pathological signaling in severe asthma. Current asthma medications, including corticosteroid therapy, are not completely effective against airway remodeling, necessitating the identification of new therapeutic targets. Targeted therapy aimed at targeting key molecular signaling pathways is emerging as a novel strategy to treat asthma [62]. Bcl10 may serve as a potential biomarker for testing the activation of NF-kB pathway in asthmatic patients and for asthma targeted therapy, taking into account its role in both airway inflammation and remodeling.

**Author Contributions:** Conceptualization, R.K.R., R.H. (Rifat Hamoudi), R.H. (Rabih Halwani) and Q.H.; Data curation, R.K.R., M.G. and Z.K.; Formal analysis, R.K.R., K.B. and R.H. (Rabih Halwani); Funding acquisition, B.M., R.H. (Rifat Hamoudi) and Q.H.; Investigation, R.K.R., K.B., M.G., M.Y.H., S.M.I. and R.H. (Rabih Halwani); Methodology, R.K.R., K.B., M.G., S.S.R., Z.K., M.Y.H., R.H. (Rifat Hamoudi) and R.H. (Rabih Halwani); Project administration, R.K.R., K.B. and Q.H.; Resources, R.H. (Rifat Hamoudi) and Q.H.; Supervision, K.B., B.M., S.M.I., R.H. (Rifat Hamoudi), R.H. (Rabih Halwani) and Q.H.; Validation, R.K.R., M.G., S.S.R. and Z.K.; Visualization, R.K.R. and S.S.R.; Writing—original draft, R.K.R.; Writing—review & editing, K.B., M.G., S.S.R., Z.K., M.Y.H., B.M., S.M.I., R.H. (Rifat Hamoudi), R.H. (Rabih Halwani) and Q.H. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was supported by the targeted research grant (2101090295), collaborative research grant (22010902103), and competitive research grant (1901090263) from the University of Sharjah, as well as the Tissue Injury and Repair group operational grant (150317), COVID-19 research grant (CoV19-0307) and collaborative research grant (2001090278) to R.H. (Rabih Halwani) from the University of Sharjah. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

**Institutional Review Board Statement:** The samples used in this study were collected from the original study that was conducted in accordance with the Declaration of Helsinki, and approved by the MUHC Research Ethics Board with reference number 2003–1879 and BMB-02-039-t.

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data presented in this study are available within the article.

**Acknowledgments:** We would like to thank Bushra Mdkhana and Swati Goel for their technical help and valuable support.

**Conflicts of Interest:** The authors declare no conflict of interest.
