Metabolic Control of Alveolar Epithelial Regeneration: Implications for Lung Repair and Pulmonary Fibrosis

Abstract

Alveolar type 2 (AT2) cells are the resident progenitors of the distal lung. They maintain tissue homeostasis and regenerate the alveolar surface after injury through coordinated self-renewal and differentiation into alveolar type 1 (AT1) cells. When this differentiation program fails, AT2 cells accumulate in aberrant intermediate states, now recognized as the epithelial “transitional state” or alveolar differentiating intermediate (ADI), a defining feature of idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases. Although the signaling pathways and transcription factors governing AT2 cell fate have been extensively characterized, the metabolic requirements for successful AT2-to-AT1 differentiation remain poorly understood. Emerging evidence indicates that AT2 cells undergo dynamic metabolic reprogramming during repair, with fatty acid oxidation, glucose metabolism, and glutamine catabolism each playing temporally distinct and mechanistically integrated roles. In IPF, AT2 cells exhibit profound mitochondrial structural abnormalities that compromise oxidative metabolism and likely underlie, at least in part, the broader pattern of metabolic dysregulation observed in diseased epithelium. This mitochondrial dysfunction, together with Warburg-like glycolytic reprogramming and impaired fatty acid oxidation, may function not only as a consequence of epithelial injury but also as a driver of differentiation failure. This review synthesizes current evidence, evaluates causal relationships among metabolic pathways, integrates metabolism with established signaling networks, and proposes a translational framework for metabolism-directed restoration of alveolar repair capacity in fibrotic lung disease.