Targeting Notch Signaling through miR-34a Modulation: Toward Precision Medicine in COPD Management

Introduction:
Chronic Obstructive Pulmonary Disease (COPD) is a progressive inflammatory lung disorder characterized by irreversible airflow limitation and systemic involvement. While previous studies have implicated microRNA-34a (miR-34a) and Notch1 in COPD pathogenesis, most were restricted to in vitro models, specific exposure types, or genetic association studies lacking clinical correlation. This study explores the diagnostic and therapeutic relevance of the miR-34a–Notch1 axis in clinically phenotyped COPD patients. Modulation of this axis using targeted oligonucleotides such as antagomir-34a, an inhibitor of miR-34a, offers potential for therapeutic intervention.

Methods:
A total of 46 participants were enrolled, comprising 23 clinically diagnosed COPD patients and 23 healthy controls, following institutional ethical approval and written informed consent. The mean age of COPD patients was 62.26 ± 9.17 years, and that of the control group was 47.05 ± 12.67 years. Group comparisons were adjusted for age using multivariate analysis to reduce confounding. Pulmonary function tests (PFTs)—including Forced Expiratory Volume in 1 second (FEV1), Forced Vital Capacity (FVC), and the FEV1/FVC ratio—were conducted alongside Diffusing Capacity of the Lung for Carbon Monoxide per unit Alveolar Volume (DLCO/VA) and Arterial Blood Gas (ABG) analysis. The serum marker Blood Urea Nitrogen (BUN) was also assessed. Expression levels of miR-34a and Notch1 were quantified using qRT-PCR.

Results:
COPD patients exhibited significant upregulation of miR-34a and downregulation of Notch1 (p < 0.001). These alterations were correlated with reduced pulmonary function and abnormal ABG parameters. Receiver Operating Characteristic (ROC) analysis revealed high diagnostic accuracy for Notch1 (AUC = 0.974) and FEV1/FVC (AUC = 0.867). ANOVA demonstrated significant variation in Notch1 expression across ABE-defined COPD subtypes, suggesting its potential utility for severity stratification.

Conclusion:
These findings support the miR-34a–Notch1 axis as a promising biomarker and therapeutic target. Antagomir-34a shows potential as a precision medicine approach for COPD management.