MICRORNA-MEDIATED GENE REGULATION IN ASTHMA: MOLECULAR PATHOGENESIS, BIOMARKERS, AND THERAPEUTIC TRANSLATION

Abstract

Background: Asthma affects more than 300 million people worldwide and remains poorly controlled in a substantial proportion of patients despite available pharmacotherapy. Heterogeneity across allergic eosinophilic, neutrophilic, and mixed endotypes underscores the need for precise molecular tools. MicroRNAs (miRNAs)—small, ~22-nucleotide non-coding RNAs—have emerged as key modulators of immune polarization, airway epithelial integrity, airway smooth-muscle remodeling, and glucocorticoid responsiveness.

Objective: This narrative review examines the mechanistic roles of major asthma-associated miRNAs, evaluates circulating and extracellular-vesicle (EV) miRNAs as clinical biomarkers, and appraises preclinical therapeutic modulation strategies.

Key Findings: Among the most consistently implicated miRNAs, miR-21 promotes Th2 polarization via IL-12p35 suppression and amplifies steroid resistance through PI3K-mediated suppression of histone deacetylase 2 (HDAC2); it also enhances PI3K-Akt signaling by targeting PTEN, contributing to airway smooth-muscle proliferation and migration. miR-155 drives eosinophilic inflammation through PU.1 suppression, while miR-146a/b exert context-dependent anti-inflammatory effects that may be attenuated during viral exacerbations. The let-7 family maintains epithelial homeostasis and is downregulated in asthmatic airways. Biomarker studies in small case-control cohorts report potentially useful diagnostic signals (e.g., AUC = 0.91 for serum exosomal miR-155 in one moderate-to-severe asthma study); these are exploratory estimates from individual studies lacking external validation. Preclinical evidence supports antagomir-21 restoration of steroid sensitivity, miR-146a mimic attenuation of rhinovirus-induced inflammation, and mucus-penetrating EV delivery of miR-511-3p reversing allergic airway inflammation in murine models.

Conclusions: No completed asthma-specific miRNA therapeutic trial was identified. Translation requires multicenter biomarker validation, standardized pre-analytical workflows, human mechanistic studies, phenotype-stratified trial designs, and reproducible pulmonary delivery systems capable of cell-specific target engagement.