MUC5B/TGF-β/KL-6 Signaling in Idiopathic Pulmonary Fibrosis: Genetic Susceptibility to Profibrotic Progression and Clinical Perspectives.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder strongly mediated by genetic susceptibility and aberrant epithelial repair mechanisms. Among the identified genetic factors, the MUC5B promoter polymorphism rs35705950 represents the most significant and frequently replicated risk variant associated with both familial and sporadic IPF. This review focuses on the mechanistic role of MUC5B dysregulation in promoting epithelial dysfunction and profibrotic signalling, with particular emphasis on its interaction with transforming growth factor-beta (TGF-β) signalling and KL-6-associated epithelial injury. Excessive MUC5B expression within distal airways disrupts mucociliary homeostasis, prolongs epithelial exposure to inhaled toxic stimuli, and enhances persistent alveolar stress, thereby facilitating chronic epithelial injury and aberrant tissue repair. Sustained epithelial damage subsequently activates TGF-β-mediated SMAD signalling pathways, promoting fibroblast activation, myofibroblast differentiation, and extracellular matrix deposition. Emerging evidence further suggests a close relationship between MUC5B-associated epithelial dysfunction and elevated KL-6 expression, indicating that KL-6 may function as a downstream biomarker indicating ongoing epithelial injury and fibrotic progression. The proposed MUC5B/TGF-β/KL-6 mechanistic signaling provides an integrated molecular network linking genetic susceptibility, epithelial dysfunction, biomarker elevation, and progressive fibrosis in IPF. In addition, telomere-related and surfactant-associated gene mutations further lead to epithelial instability and impaired regenerative capacity. Together, these interconnected molecular mechanisms provide significant insights into IPF progression and may support the development of biomarker-driven prognostic approaches and targeted precision therapies for improved disease management.