Treatment-Resistant Severe Asthma Phenotype with Dysregulated Hippo Pathway

This study examines immunological, transcriptional, and proteomic biomarkers in patients with severe asthma from the Brazilian ProAR cohort. Sputum transcriptomics was performed by RNA-seq using the Ion S5 next-generation sequencing platform (ThermoFisher). Compared to mild-to-moderate asthma (MMA) and treatment-controlled severe asthma (SAC), the treatment-resistant Severe Asthma (SAR) group exhibited increased sputum neutrophilia, eosinophilia, and elevated IL-6 and TNF levels, correlating with impaired lung function. Transcriptomic and proteomic analyses revealed a Th2-independent molecular signature characterized by downregulation of the Hippo signaling pathway and upregulation of JAK-STAT inflammatory cascades. Distinctive microRNA profiles suggest regulatory involvement in inflammatory and proliferative processes. These findings align with prior studies, reinforcing the presence of an IL-6 and TNF-high severe asthma phenotype across diverse populations.