Telomere-associated non-malignant pulmonary diseases: Pathogenic mechanisms and therapeutic strategies

Telomeres and telomerase have been extensively implicated in the cellular processes of aging and inflammation. Recent studies have shown that telomere length (TL), the shelterin complex, and telomerase dysfunction are closely related to non-malignant pulmonary diseases including interstitial lung diseases (ILD), chronic obstructive pulmonary disease (COPD), and asthma. Short telomere defects with or without mutations in telomere maintenance genes and telomerase are relatively common, affecting the progression of non-malignant pulmonary diseases, explaining disease susceptibility, and revealing clinically relevant manifestations. In this review, we examine the biological characteristics and functions of telomeres and telomerase, and investigate the intricate relationship between changes in TL and mutations in telomerase genes in non-malignant pulmonary diseases after a detailed associated literature review. Subsequently, we focus on the clinical features of non-malignant pulmonary diseases related to dysfunctional telomeres/telomerase, as well as the potential molecular mechanisms underlying these associations, along with the current status of therapeutic interventions. Finally, we delineate current knowledge gaps and transformative opportunities in telomere biology research, with a focus on bridging molecular discoveries to clinical innovations for telomere-associated non-malignant pulmonary diseases, aiming to accelerate the development of precision diagnostic tools and mechanism-based therapeutics.