Abstract Rarionale Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease (ILD) characterized by abnormal activation and proliferation of lung fibroblasts as a key effector process. Due to the irreversible nature of pulmonary fibrosis, IPF has a very poor prognosis. Current therapeutic drugs cannot reverse fibrosis or prolong patient survival, imposing a heavy socioeconomic burden. Therefore, it is urgent to deeply understand the pathogenesis of IPF and identify new therapeutic targets. Prostate transmembrane protein androgen induced 1 (PMEPA1) regulates the growth and metastasis of various tumors and is closely associated with the TGF-β signaling pathway. It serves as a biomarker and potential therapeutic target for multiple tumors, but its role in IPF, which shares pathogenic mechanisms with tumors, remains unclear. This project aims to investigate the mechanism by which PMEPA1 regulates lung fibroblasts in pulmonary fibrosis and explore its clinical translational potential as a therapeutic target. Methods Single-cell sequencing data of lung tissues from IPF patients were analyzed, and PMEPA1 expression and distribution were further examined in IPF patient lung tissues and mouse pulmonary fibrosis models. Pmepa1 knockout mice were generated, and precision cut lung slice (PCLS) was used to create organoid models to study the effect of PMEPA1 on the severity of pulmonary fibrosis induced by bleomycin (BLM)/Transforming growth factor-beta 1 (TGF-β). The functional and molecular regulatory roles of PMEPA1 in primary lung fibroblasts from IPF patients were investigated. Fibroblast-activating protein ligand (FAPL)-modified lipid nanoparticles (LNP) were constructed to deliver small interfering RNA (siRNA) of PMEPA1 and dihydromyricetin (DHM), a PMEPA1 inhibitor, with Dir labeling for tracking, to explore clinical translational therapy in a mouse pulmonary fibrosis model. Results The level of PMEPA1 was significantly elevated in lung fibroblasts of IPF patients and mouse pulmonary fibrosis models. TGF-β1 promoted the level of PMEPA1 in fibroblasts in vitro. PMEPA1 regulated the differentiation, proliferation, migration, mitochondrial respiration, and glucose transport functions of primary lung fibroblasts via the STAT3/p-STAT3/GLUT1 pathway, thereby contributing to pulmonary fibrosis. Pmepa1 knockout significantly alleviated the severity of BLM/TGF-β-induced pulmonary fibrosis in mice. In vivo, FAPL-modified LNP successfully delivered siRNA/DHM to fibrotic lung regions and markedly reduced BLM-induced pulmonary fibrosis in mice. Conclusion PMEPA1 regulates fibroblast functions through the STAT3/p-STAT3/GLUT1 signaling pathway and participates in the progression of pulmonary fibrosis. Modulating PMEPA1 expression in lung fibroblasts can alter the progression of pulmonary fibrosis, making PMEPA1 a promising new target for IPF treatment with clinical potential. This abstract is funded by: National Natural Science Foundation of China (No. 82200074)
Hu et al. (Fri,) studied this question.