PRDX4 regulates AMs cell activity through the AKT/NF-κB pathway to inhibit the progress of pulmonary fibrosis

Abstract

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a fatal disease that leads to severe lung fibrosis, and PRDX4 expressed highly in AMs may be closely related to the process of fibrosis progression. This study investigates the function and molecular mechanisms of the potential therapeutic target PRDX4 in idiopathic pulmonary fibrosis (IPF). Methods This study utilized single-cell RNA sequencing (scRNA-seq) of lung tissue, transcriptome sequencing (RNA-Seq) of bronchoalveolar lavage fluid (BALF), and clinical data retrieval to investigate key cells influencing inflammation and fibrosis in patients with idiopathic pulmonary fibrosis (IPF), and to analyze the expression and prognostic value of PRDXs. AAV-mediated knockdown of PRDX4 protein expression was performed specifically in alveolar macrophages (AMs) of IPF mice, and lung function as well as changes in inflammatory and fibrotic gene expression were evaluated. In vitro cell experiments and tissue immunofluorescence were conducted to investigate the regulatory mechanisms of PRDX4 both in vivo and in vitro. Results Alveolar macrophages (AMs) and type II lung epithelial cells (AT2) are the major contributing cells for inflammation and fibrosis genes in lung tissue of IPF patients. High expression of PRDX4 in AMs is significantly negatively correlated with patient prognosis (p < 0.05). Functionally, knockdown of PRDX4 expression in AMs effectively improves lung function (EF50, VT, and MV) in IPF mice, while inhibiting the expression of genes related to lung inflammation and fibrosis. Mechanistically, PRDX4 can regulate the secretion of inflammation-related factors in AMs through the AKT/NF-κB pathway, thereby inhibiting the progression of inflammation and fibrosis in IPF mice. Conclusions Inhibiting the expression of PRDX4 in alveolar macrophages (AMs) can modulate the activity of these cells, thereby suppressing the progression of IPF disease.