The context-dependent roles of ATG5 in age-related lung diseases

Lung aging, characterized by the decline in lung structure and function, increases the susceptibility to age-related lung diseases. Autophagy-related 5 (ATG5) is a critical protein of the autophagy machinery and exhibits remarkably complex functions in the aging lung. Depending on the biological context, ATG5-associated processes may promote either cellular homeostasis and tissue repair or inflammation and tissue remodeling. In this review, we propose a context-dependent conceptual framework to explain the diverse roles of ATG5 in age-related lung diseases. Distinct ATG5-associated substrates and mechanisms produce different biological effects, while cellular states and disease stages influence which mechanisms predominate. We further highlight precision strategies for therapeutic modulation of ATG5, including context-dependent regulatory mechanisms, pharmacological approaches, targeted delivery, the potential role of artificial intelligence, and clinical translation. A comprehensive understanding of when, where, and how ATG5 should be modulated may open new avenues for precision pharmacotherapy and ultimately improve the treatment of age-related lung diseases.