Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive alveolar type 2 (AT2) cell dysfunction, impaired lung repair, and excessive fibrosis, with limited treatment options. AT2 cells, critical stem cells for alveolar maintenance, produce pulmonary surfactant rich in phosphatidylcholine (PC), modulated by lysophosphatidylcholine acyltransferase 1 (LPCAT1). Dysregulated PC concentrations have been observed in various respiratory disorders, including IPF. However, the precise roles of phospholipid metabolism in AT2 cell regeneration and the progression of pulmonary fibrosis remain incompletely understood. In this study, we elucidate the role of LPCAT1 in AT2 renewal and IPF pathogenesis using advanced molecular and pharmacological approaches. Single-cell RNA sequencing, qPCR, Western blot, and immunofluorescence consistently revealed significant LPCAT1 downregulation in AT2 cells from IPF patients and bleomycin-injured mouse models compared with controls. In an AT2-specific Lpcat1-deficient mouse model (Sftpc-CreER;Lpcat1flox/flox), we observed spontaneous lung fibrosis, reduced AT2 renewal, and increased collagen deposition post-bleomycin injury. Lipidomic analyses, including PC quantifications and shotgun lipidomic assays, demonstrated disrupted PC levels and lipid profiles in LPCAT1-deficient AT2 cells, impairing mitochondrial function, as evidenced by Seahorse metabolic assays. In 3D organoid cultures, LPCAT1 inhibition reduced AT2 colony-forming efficiency, highlighting its indispensable function in progenitor activity. Conversely, CRISPR-mediated LPCAT1 overexpression in IPF-derived AT2 cell lines restored PC levels, enhanced AT2 self-renewal, and improved mitochondrial respiration. High-content drug screening identified candidates that upregulated LPCAT1 expression, promoted AT2 renewal, and attenuated bleomycin-induced fibrosis in vivo. These findings establish LPCAT1 as a pivotal regulator of AT2 progenitor function and lipid metabolism, with its deficiency exacerbating fibrotic injury. Reactivation of LPCAT1 restored AT2 regenerative capacity and mitigated fibrosis, suggesting a novel therapeutic strategy for IPF. By targeting LPCAT1-mediated lipid metabolism, it may be possible to enhance alveolar repair, halt disease progression, and offer hope for addressing this devastating disease. This abstract is funded by: NIH
Rabata et al. (Fri,) studied this question.