Cystic fibrosis: insights from zebrafish models

Cystic fibrosis (CF) is a severe, life-limiting genetic disorder caused by mutations in the CFTR gene, which lead to defective epithelial ion transport, abnormally thick mucus and multi organ dysfunction, predominantly affecting the lungs, pancreas and digestive system. Despite significant advances in patient care, the complex interplay between CFTR dysfunction, chronic infection and persistent inflammation remains a major therapeutic challenge. In this context, animal models are indispensable for elucidating the cellular and molecular mechanisms underlying CF pathogenesis and accelerating drug discovery. Here, we review the relevance of the zebrafish (Danio rerio) as a powerful and complementary preclinical model for CF research. In particular, we highlight the unique advantages of zebrafish, including its highly conserved innate immune system and optical transparency, which together enable in vivo visualization of host immune responses under CF-like conditions at subcellular resolution. We further summarize how Cftr-deficient zebrafish models have provided key insights into the increased susceptibility to CF-relevant pathogens, disease mechanisms affecting the pancreas and the reproductive system, and the deleterious neutrophil-driven inflammation that characterizes CF. Finally, we discuss the potential of the zebrafish model for the identification and validation of novel therapeutic strategies to treat infectious and inflammatory lung pathology in CF, and outline future directions to expand its translational impact in CF research.