Autophagy in the lung: guardian of homeostasis or driver of disease.

Abstract

Autophagy is a lysosome-directed recycling program that preserves lung homeostasis yet, when dysregulated, can cause disease. This review organizes current evidence by lung compartment and disease phase, proposing that autophagy polarity is determined by cell identity, micro-niche, and timing along the injury-repair continuum. In chronic obstructive pulmonary disease, epithelial autophagy is initially cytoprotective, but chronic smoke exposure reveals a lysosome bottleneck and stalled flux, while alveolar macrophages show impaired xenophagy and poor acidification. In idiopathic pulmonary fibrosis, autophagy is suppressed in type II epithelial cells and fibroblasts downstream of transforming growth factor beta (TGF-β) and mTORC1, which promotes epithelial stress programs and collagen translation. In acute lung injury and respiratory distress syndrome, timely autophagy activation limits cGAS-STING and NLRP3 signaling, preserves barrier integrity, and supports recovery. In asthma, autophagy supports mucin biogenesis in epithelial cells but is reduced in antigen-presenting cells, while eosinophil and mast cell effector functions rely on autophagy. In infection, xenophagy clears microbes but is actively subverted by bacteria and respiratory viruses. In non-small cell lung cancer (NSCLC), tumor-intrinsic autophagy maintains energy metabolism, redox balance, and enables immune evasion, whereas host autophagy can alternately support antitumor immunity or supply nutrients. We summarize small-molecule modulators, delivery strategies, and flux-aware tools that enable precise, cell- and phase-resolved modulation of autophagy to guide patient selection and improve therapy in respiratory disease.