MicroRNAs in Cystic Fibrosis: Dual Role in Pathogenesis and Therapeutic Potential

Cystic fibrosis (CF) is a severe inherited disorder caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial ion channel essential for maintaining airway surface hydration and effective mucociliary clearance. Although over a thousand CFTR mutations have been described, their functional consequences vary widely, with some genotypes retaining partial CFTR activity and presenting as residual-function phenotypes. Despite CFTR modulator therapies substantially improved clinical outcomes in many patients, their efficacy remains incomplete and strongly dependent on the underlying CFTR mutation. Increasing evidence indicates that microRNAs (miRNAs), as key post-transcriptional regulators of gene expression, play a dual role in CF by contributing to disease pathogenesis while also representing potential therapeutic targets. This review provides an overview of the involvement of miRNAs in CF pathophysiology, with emphasis on their roles in CFTR regulation, airway inflammation, epithelial ion transport, and mucus homeostasis. Experimental findings demonstrating that modulation of specific miRNAs enhances CFTR mRNA stability and protein expression, attenuates pro-inflammatory signaling, and improves epithelial function are discussed. Current miRNA-based therapeutic strategies and their translational challenges are discussed, along with their potential integration with emerging CF therapies, including CFTR modulators, mRNA replacement, antisense oligonucleotides, and suppressor tRNA strategies. Given the predominantly preclinical evidence, miRNA modulation may offer a mutation-independent approach to complement existing therapeutic strategies. A combination of miRNA-based approaches with established CF therapies may represent a potential complementary strategy, but the efficacy and safety of such combinations require further experimental and clinical validation.