Mus musculus Transcriptome or Gene expression

Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes significantly diminishes in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition in alveolar type 2 (AT2) cells of aberrant intermediate states co-expressing alveolar type 2 (AT2), alveolar type 1 (AT1), and airway epithelial cell markers including KRT17, SCGB1A1, and SCGB3A2. Further, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of alveolar epithelial cells expressing high levels of alveolar differentiation intermediate cells, airway secretory cells, and senescence markers. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-beta signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.