Mechanisms of lung regeneration and repair

The adult lung maintains tissue integrity through adaptable regenerative programs that rely on the plasticity of epithelial progenitor cells across airway and alveolar compartments. Rather than following a linear stem-cell hierarchy, regeneration is driven by context-dependent lineage behaviors shaped by local signaling pathways, metabolic state, epigenetic regulation, and biophysical cues. Basal cells are the main stem cells of the airway epithelium, whereas alveolar type 2 cells act as the stem cells in the alveoli and regenerate the gas-exchange surface through defined transitional states. These processes are regulated by main signaling networks, including Wnt/β-catenin, Notch, fibroblast growth factor, bone morphogenetic protein / SMAD family proteins, and Hippo-Yes-assciated protein / transcriptional co-activator with PDZ-binding motif, which integrate niche-derived signals and mechanical inputs to control stem/progenitor activation and fate decisions. Disruption or persistence of these signaling networks leads to inefficient or aberrant repair and contributes to chronic lung disease. This review summarizes recent findings in cellular and molecular mechanisms of lung regeneration and highlights how controlled epithelial plasticity determines the balance between effective repair and disease-associated outcomes.