PMEPA1 Participates In The Pathogenesis Of Pulmonary Fibrosis By Regulating STAT3/p-STAT3/GLUT1 Signaling Pathway

Background:Idiopathic pulmonary fibrosis(IPF)is a kind of Interstitial lung disease(ILD)characterized by pulmonary fibrosis with an unknown cause.Due to the irreversibility of pulmonary fibrosis,IPF has become the most aggressive ILD disease.Although several drugs that can delay the progression of fibrosis have been used in clinic treatment,they cannot extend the life span of IPF patients.Therefore,it is in great urgent to deeply understand the pathogenesis of IPF and find new therapeutic targets for IPF.Prostate transmembrane protein androgen induced 1(PMEPA1)is first discovered in prostate cancer,and subsequent studies have shown that PMEPA1 is a kind of protein widely expressed in neoplastic diseases.The expression level of PMEPA1 has multiple effects on tumor growth and metastasis.It can be used as a biomarker and potential therapeutic target for a variety of tumors,but its effects on the pathogenesis of IPF remains unclear.Objective:To investigate the expression of PMEPA1 in lung tissues of IPF patients,primary lung fibroblasts and mice with pulmonary fibrosis induced by Bleomycin(BLM).To clarify the regulatory effects of PMEPA1 on the differentiation,proliferation,migration and other functions of fibroblast.To explore the molecular mechanism of PMEPA1 in regulating fibroblast function and pulmonary fibrosis.To explore the feasibility of PMEPA1 as a therapeutic target for pulmonary fibrosis in bleomycin mice.Methods:Single cell sequencing data of IPF lung tissue were retrieved to analyze the expression level of PMEPA1 in IPF and donor lung fibroblasts.The pulmonary tissues of IPF patients and donor mice were collected and BLM was used to induce the formation of pulmonary fibrosis in mice.The differences in the expression of PMEPA1 in the pulmonary tissues of IPF patients,donor mice and BLM-induced pulmonary fibrosis mice were detected by immunofluorescence co-staining and Western blot.Primary lung fibroblasts were isolated and cultured in vitro to explore the regulatory effects on differentiation,proliferation,migration and other functions the and underlying mechanisms of PMEPA1.PMEPA1 knockout mice were constructed to explore the effect of PMEPA1 on the severity of pulmonary fibrosis in BLM induced mice model.Dihydromyricetin(DHM)was administered to BLM mice to observe the therapeutic effect of DHM on pulmonary fibrosis.Results:The single-cell sequencing data showed that the level of PMEPA1 in lung fibroblasts of IPF patients was significantly higher than that of donor lung fibroblasts,and the expression level of PMEPA1 in lung tissues of IPF patients and BLM mice model was also significantly increased.Transforming growth factor-beta 1(TGF-β1)could promote the expression of PMEPA1 in fibroblast in vitro.PMEPA1 could regulate the differentiation,proliferation,migration functions of fibroblasts.PMEPA1 gene knockout can also significantly reduce the severity of pulmonary fibrosis in BLM induced mice.DHM can inhibit the expression of PMEPA1 in fibroblasts,and inhibit the differentiation,proliferation,migration,and respiratory function of fibroblasts.Meanwhile,DHM can also reduce the severity of pulmonary fibrosis in BLM mouse models.Signaling pathway studies have shown that PMEPA1 regulates fibroblast function and participates in pulmonary fibrosis through the STAT3/p-STAT3/GLUT1 signaling pathway.Conclusion:PMEPA1 can regulate the functions of fibroblast through STAT3/pSTAT3/GLUT1 signaling pathway and participate in the process of pulmonary fibrosis.Regulating the expression of PMEPA1 in lung fibroblasts can change the progression of pulmonary fibrosis,and PMEPA1 is expected to be a new target for IPF treatment.