Autophagy as a Redox Rheostat Linking Cigarette Smoke, Electronic Cigarettes, and Nicotine Exposure to Lung Development, Disease, and Interorgan Communication.

Autophagy is a central cellular quality-control pathway that maintains metabolic and proteostatic homeostasis by degrading damaged organelles and proteins. In the lung, autophagy contributes to normal development, epithelial integrity, mitochondrial quality control, and immune regulation. Emerging evidence indicates that environmental exposures such as cigarette smoke (CS), electronic cigarette (EC) aerosols, and nicotine profoundly disrupt these processes, contributing to both chronic lung disease and developmental programming of respiratory pathology. In this review, we propose a unifying framework in which autophagy functions as a redox-modulated rheostat that integrates oxidative, metabolic, and epigenetic stress signals triggered by smoke and nicotine exposure. Under physiological conditions, autophagy mitigates oxidative stress by removing dysfunctional mitochondria and maintaining proteostasis. However, chronic exposure to CS or EC aerosols generates excessive reactive oxygen species, impairs lysosomal degradation, and disrupts mitochondrial quality control, shifting autophagy from an adaptive protective response to a maladaptive driver of epithelial injury, inflammation, and tissue remodeling. Integrating experimental and clinical evidence, we identify four mechanistic axes underlying smoke-induced autophagy dysregulation: lysosomal dysfunction with TFEB suppression, mitochondrial redox amplification, disruption of selective autophagy pathways (including mitophagy, ER-phagy, xenophagy, and lipophagy), and immune polarization associated with inflammasome activation and cellular senescence. Importantly, maternal smoke and EC exposure similarly perturb autophagy in the placenta and fetal lung, altering developmental trajectories and increasing susceptibility to asthma and chronic lung disease. Viewing autophagy as a dynamic, redox-sensitive rheostat highlights new therapeutic opportunities to restore autophagic flux, lysosomal competence, and mitochondrial quality control in smoke- and nicotine-related lung disease.