DLK1 downregulation serves as a potential biomarker for disease severity and a therapeutic target in bronchiectasis

Abstract Background The pathological mechanisms underlying bronchiectasis remain incompletely understood, necessitating novel therapeutic targets. Delta-like homolog 1 (DLK1), a Notch pathway regulator, plays critical roles in tissue repair and inflammation modulation, yet its regulatory role in bronchiectasis pathogenesis remains undefined. Methods This study integrated cis-expression quantitative trait loci data of the DLK1 gene, plasma protein quantitative trait loci data, and bronchiectasis genome-wide association study summary statistics from the FinnGen database (cases = 2,597; controls = 372,627). Using a two-sample Mendelian randomization (MR) approach, it aimed to systematically evaluate the potential causal relationship between DLK1 gene expression levels and the risk of bronchiectasis development. Peripheral blood DLK1 mRNA levels were measured in 20 bronchiectasis patients and 20 healthy controls, with correlations assessed against clinical phenotypes and Bronchiectasis Severity Index (BSI). Results MR analysis revealed that each 1-standard deviation decrease in DLK1 gene expression increased bronchiectasis risk by 28% (IVW OR = 0.722, 95%CI: 0.562–0.932, P = 0.010). Reduced DLK1 protein levels also significantly correlated with elevated risk (IVW OR = 0.924, 95%CI: 0.860–0.993, P = 0.031). MR-Egger intercept (P = 0.256) and Cochran’s Q test (P = 0.398) indicated no horizontal pleiotropy or heterogeneity. Clinical validation demonstrated significantly lower DLK1 mRNA expression in patients versus controls (P = 0.009), with further reduction in severe BSI subgroups (P = 0.002). Conclusions This study provides the first genetic evidence that DLK1 downregulation drives bronchiectasis progression, with expression levels inversely correlating with disease severity. DLK1 emerges as a potential diagnostic biomarker and therapeutic target, offering insights for precision medicine strategies.