Lysosome-autophagy networks in lung development, maturation, and pediatric lung disease

Lysosomes are increasingly recognized as dynamic regulatory organelles that integrate degradation, nutrient sensing, lipid metabolism, membrane trafficking, and organelle quality control beyond their classical degradative functions. These activities are particularly important during lung development, when epithelial differentiation, alveolarization, lung maturation, surfactant homeostasis, and postnatal adaptation occur within a narrow developmental window. This review summarizes current evidence linking lysosome-autophagy networks to lung maturation, with emphasis on epithelial autophagy, alveolar type II (AT-II) cell function, lamellar-body biology, mitochondrial quality control, and alveolar macrophage regulation. We discuss how lysosomal lipid handling, autophagic flux, and mechanistic target of rapamycin (mTOR)-transcription factor EB (TFEB) signaling contribute to developmental homeostasis while distinguishing direct pulmonary evidence from mechanistic hypotheses derived from other systems. We further examine lysosomal and autophagic alterations in pediatric lung diseases, including bronchopulmonary dysplasia, cystic fibrosis, and viral respiratory infection, highlighting disease-specific upstream stressors and intracellular defects. Static autophagy markers cannot define functional flux, and conventional lysosomes must be distinguished from specialized lysosome-related organelles such as lamellar bodies. Finally, we discuss therapeutic opportunities and challenges, emphasizing cell-specific targeting, restoration of defined organelle defects, developmental safety, and rigorous functional validation. A developmentally informed understanding of lysosome-autophagy networks may provide new mechanistic frameworks for pediatric lung disease intervention.