ABSTRACT:
This study utilized a comprehensive bioinformatic framework to investigate transcriptomic differences between mild-to-moderate and severe asthma, aiming to map key pathways, regulatory hubs, and potential drug repurposing candidates. Publicly available transcriptomic data were processed using DESeq2 in R to identify differentially expressed genes. We constructed Protein–Protein Interaction (PPI) networks visualized via STRING and Cytoscape, and performed functional enrichment for Gene Ontology and KEGG pathways. Upstream regulatory analysis was conducted using ChEA to predict transcription factor activity. In mild-to-moderate asthma, upregulated signatures were intrinsically linked to adaptive immune priming, epithelial regeneration, and metabolic regulation. Key genes including CREM, NFIL3, NR4A2, and IGF1 pointed toward active tissue repair mechanisms, orchestrated by transcription factors such as STAT5A, SOX2, and SMAD3. Conversely, the transcriptomic landscape of severe asthma revealed a distinct transition toward innate immune dominance and hypoxia adaptation. The significant elevation of hemoglobin genes and neutrophil-associated mediators like S100A12, DEFA3, and SERPINB3 indicates a hypoxic, oxidative environment driven by stress-response factors including TP53 and GATA2. Network topology analysis highlighted two non-overlapping dominant hubs: a proliferative/repair module in mild cases versus a hemoglobin-rich inflammatory module in severe disease (p < 1.0 × 10⁻¹⁶). Furthermore, drug–gene interaction mapping suggested that targeting EGFR, NAMPT, and PDE4B could offer therapeutic avenues to reverse these specific pathological states. Conclusively, these findings demonstrate that asthma progression represents a molecular departure from coordinated adaptive repair toward a dysregulated, hypoxic innate inflammatory state, providing a robust foundation for novel biomarker validation and therapeutic strategy development.