FPPS Downregulation Attenuates Endoplasmic Reticulum Stress in Pulmonary Epithelial Cells

ABSTRACT The airway epithelium is the primary target of the trachea in lung transplant rejection and epithelial cell injury are frequently observed in lung transplants. Farnesyl pyrophosphate synthase (FPPS), a pivotal enzyme in the mevalonate pathway, synthesizes isoprenoid compounds like FPP and GGPP. This study found upregulated expression of FPPS in the epithelial cells of the tracheal transplant rat model and the use of the FPPS inhibitor zoledronic acid reduced the tracheal epithelial cell damage. Using CRISPR/CAS9, FPPS was knocked down in pulmonary‐derived epithelial cells, and RNA sequencing analysis revealed alterations in the gene expression profile, notably involving significant reductions in multiple endoplasmic reticulum stress‐related genes, including the ATF4/TRIB3 pathway and the ERN1/XBP1 pathway, which were further confirmed at the protein level. Additionally, treatment with zoledronic acid exhibited inhibitory effects on endoplasmic reticulum stress in the tracheal transplant rat model. Furthermore, FPPS knockdown and Inhibition were found to suppress the expression of multiple amino acid transporters, including SLC7A5, resulting in decreased intracellular levels of multiple amino acids, reduced mTORC1 pathway activity, and enhanced autophagic function. In summary, this study identified the protective roles of FPPS inhibition in epithelial cells of the tracheal transplant model, potentially mediated through reductions in endoplasmic reticulum stress, decreased mTORC1 activity, and augmented downstream autophagic processes.