Peroxiredoxin 4 as a switch regulating PTEN/AKT axis in alveolar macrophages activation.

Phosphatase and tensin homolog (PTEN) is a critical inhibitor of the PI3K/AKT signaling pathway, yet its direct upstream regulators remain poorly defined. In this study, we investigated the role of peroxiredoxin 4 (PRDX4) in alveolar macrophages (AMs) activation and pulmonary fibrosis. Analyses of lung tissues from silicosis patients by transcriptomic and histological analyses revealed that PRDX4 is selectively upregulated in AMs and positively correlated with profibrotic and inflammatory gene expression. Consistent results were observed in silicosis model mice, where PRDX4 expression co-localized with the macrophage marker F4/80 and correlated with fibrotic indicators. Functional studies demonstrated that macrophage-specific silencing of PRDX4 using adeno-associated virus improved lung function and reduced inflammatory infiltration and fibrosis. PRDX4 upregulation aberrantly activated AMs and promoted epithelial-mesenchymal transition and fibroblast-myofibroblast transition. Mechanistically, PRDX4 enhanced AKT/NF-κB signaling with minimal effects on PI3K. Biochemical interaction assays further demonstrated that oligomeric PRDX4 disrupted PTEN homodimer formation, with mutational analyses identifying Cys124 and Cys245 as essential residues. Notably, Conoidin A alleviated crystalline silica-induced fibrosis in mice, with its therapeutic effect likely mediated by disrupting PRDX4 oligomerization. These findings identify PRDX4 as a novel upstream regulator of PTEN, establish a mechanistic PRDX4-PTEN axis in macrophage activation, and highlight PRDX4 as a promising therapeutic target for idiopathic pulmonary fibrosis and silicosis-associated fibrosis.