Abstract Idiopathic Pulmonary Fibrosis (IPF) is an age-related and progressive lung disease characterized by loss of the normal alveolar architecture and accumulation of scarring tissue replacing the functional lung parenchyma. One of the main characteristics is the loss of alveolar epithelial type II stem cells (AT2), with the concurrence appearance of transitional AT2 cells. This aberrant alveolar epithelial cell co-expresses genes of AT2, AT1, and airway epithelial cells simultaneously. Although transient AT2 epithelial cells are enriched in areas of severe fibrosis, the mechanisms involved in remodeling and lung fibrosis remain poorly understood. Our preliminary data show that under normal conditions, AT2 actively metabolizes long fatty acids by fatty acid oxidation (FAO). As the mitochondrial membrane is impermeable to acyl-CoA FA, the outer membrane mitochondrial protein, carnitine palmitoyltransferase 1A/1B (CPT1a/CPT1b), catalyzes transport step of the lipid metabolism been the limiting rate of this pathway. In the lung, in AT2 from aging and IPF lungs, there is a decrease in the expression of the CPT1a with reduced levels of Acetyl CoA, an FAO metabolite. To determine if FAO is essential for the repair responses, we developed CPT1a deficient cell lines and a conditional AT2-CPT1a deficient mouse. Using these tools, we have found that: 1) expression and activity of CPT1a in AT2 cells is required for the protection against injury-induced lung fibrosis, 2) deficiency of CPT1a enhances markers of transitional AT2 stem cells, with markers of TGFβ1 activation, and cellular senescence, 3) CPT1a regulates TGF- β1 signaling by acetylation and degradation of the negative regulator Smad7, and 4) deficiency of CPT1a engages histone hypoacetylation in lung epithelial cells. These observations have led to the hypothesis that FAO regulates AT2 differentiation by epigenetic reprogramming via modulation of acetyl-CoA levels. A deficiency of FAO triggers AT2 differentiation into a transient aberrant AT2 without reaching a terminal AT1 differentiation, decreasing the resilience against lung fibrosis. To evaluate this hypothesis, we propose the following aims: Aim 1. To examine the hypothesis that acetyl-CoA FAO generated in AT2 cells regulates epigenetically and transcriptionally AT2 differentiation. Acetyl CoA generated in the mitochondria via FAO is an essential metabolite linking metabolic and nuclear programs influencing AT2 differentiation. Aim 2. To test the hypothesis that AT2 CPT1a expression confers resilience against the development of lung fibrosis. Our preliminary data show defective FAO in aging AT2 cells, and deficiency of CPT1a/FAO in AT2 increases susceptibility to tissue remodeling associated with pulmonary fibrosis. Completion of these aims will enhance our understanding of the role of CPT1a and FAO in the wound healing process and age-related mechanisms of resilience to disrepair and fibrosis.