Fibroblast Growth Factor Signaling in Lung Diseases: From Biological Roles to Therapeutic Delivery Strategies.

Abstract

As human longevity continues to increase globally, the prevalence of age-related deterioration and associated chronic lung diseases has risen in parallel. Unlike many organs, the lung is continuously exposed to environmental insults, leading to cumulative cellular damage, impaired epithelial progenitor activity, and chronic inflammation, which contribute to diseases such as pulmonary fibrosis and chronic obstructive pulmonary disease. Under physiological conditions, lung homeostasis is maintained by epithelial progenitor cells, particularly alveolar type II cells. However, this regenerative capacity is often disrupted in chronic lung diseases, resulting in impaired repair and fibrotic remodeling. Fibroblast growth factors (FGFs) and their receptors (FGFRs) play critical roles in epithelial regeneration, cell survival, and tissue repair. Despite their therapeutic potential, clinical translation remains limited by poor protein stability, rapid proteolytic degradation, low delivery efficiency across biological barriers, and insufficient cell-type specificity due to broad FGFR expression. Recently, several delivery strategies have been evaluated in preclinical lung disease models, including protein engineering, nanoparticle and liposome-based platforms, protein transduction domain- and cell-penetrating peptide-based intracellular delivery, and mesenchymal stem cell-based approaches. Therefore, this review summarizes the roles of FGF signaling in lung regeneration and age-associated diseases, and discusses emerging delivery strategies aimed at bridging the gap between preclinical efficacy and clinical application.