Transcriptomic Analysis Reveals microRNA Therapeutic Candidates Targeting Chronic Airway Inflammation in Cystic Fibrosis ^†

Introduction: Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CFTR gene, resulting in a production of abnormally thick secretions, chronic airway inflammation, and severe respiratory complications. Despite advances with CFTR modulators, these therapies have limitations, highlighting the need for new therapeutic strategies. Methodology: This study sought to identify differentially expressed genes (DEGs) in respiratory epithelial samples from CF patients, as well as to prioritize regulatory microRNAs for potential in silico therapeutic approaches. Data from the GSE30439 series, available in the Gene Expression Omnibus (GEO), were analyzed with the limma package in R software. Genes with FDR < 0.05 and |log2FC| ≥ 1 were considered DEGs and subjected to functional enrichment analyses. Subsequently, regulatory miRNAs were identified using prediction and validation databases, with mimics and antimiRs proposed for the most promising candidates. Results: The study showed that bronchial epithelial cells from patients have an altered gene expression profile, marked by inflammatory hyperactivation and tissue remodeling. The analysis identified miRNAs that regulate this pathway, including miR-17-5p, miR-106b-5p, and miR-203b-3p, which emerge as promising candidates for therapeutic strategies based on mimics/antimiRs aimed at reducing chronic inflammation. Based on these results, standardized anti-miR oligonucleotides and mimics were also designed, generating a set of miRNAs with high anti-inflammatory potential. Conclusions: Finally, these findings are important because they broaden the understanding of the molecular basis of chronic inflammation in CF and point to miRNAs as new targets for innovative therapies beyond CFTR correction.