Autophagy influences DNA damage: a potential therapeutic approach for chronic respiratory diseases

Chronic respiratory diseases (CRDs), including pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), asthma, and lung cancer, are sustained by recurrent epithelial injury, oxidative stress, inflammation, and defective tissue repair. DNA damage and dysregulated autophagy are common pathophysiological features of CRDs, but their mechanistic crosstalk has not been integrated across disease contexts. This narrative review examines how autophagy shapes pulmonary genomic stability by removing dysfunctional mitochondria and other organelles, limiting reactive oxygen species, regulating iron and antioxidant homeostasis, controlling Sequestosome 1 (p62/SQSTM1) and DNA damage response (DDR) proteins, clearing damaged nuclear material, supplying metabolic substrates for DNA repair, and preserving centrosome and chromosome integrity. The direction of this effect is cell- and stage-dependent: impaired autophagic flux or mitophagy predominates in PF and COPD, selected asthma cell populations exhibit excessive pro-inflammatory autophagy, and lung cancer illustrates a transition from genome-protective autophagy in non-transformed pulmonary epithelium to heterogeneous stress-adaptive autophagy in transformed cells and stromal compartments. We therefore argue that the key determinant is the appropriate regulation of autophagic flux in a cell- and disease stage-dependent manner, rather than simply increasing or decreasing autophagic activity. Major gaps include limited simultaneous measurement of flux and DNA lesions, insufficient cell-specific causal studies in human lung models, and uncertainty over whether autophagy abnormalities are drivers or consequences of persistent DDR. The modulation of the autophagy-DNA damage axis warrants further preclinical evaluation as a strategy to preserve pulmonary tissue homeostasis.