2. Academic Validation
  3. Peroxiredoxin 4 as a switch regulating PTEN/AKT axis in alveolar macrophages activation

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

  • Signal Transduct Target Ther. 2025 Oct 24;10(1):352. doi: 10.1038/s41392-025-02454-x.
Jia-Wei Zhou # 1 2 3,  Ying Bai # 1 2 3,  Jian-Qiang Guo # 1 3,  Yun-Yun Li 1 3,  Ya-Feng Liu 1 3,  Chao Liang 1 3,  Ying-Ru Xing 3 4 5,  Hai-Long Guo 6,  Tian-Xiang Qi 7 8,  Jing Wu 9 10 11,  Dong Hu 12 13 14 15
Affiliations

Affiliations

  • 1 Department of immunology, School of Medicine, Anhui University of Science and Technology, Huainan, China.
  • 2 Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 3 Anhui Occupational Health and Safety Engineering Laboratory, Huainan, China.
  • 4 Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, China.
  • 5 Cancer Hospital of Anhui University of Science and Technology, Huainan, China.
  • 6 Occupational Control Hospital of Huaihe Energy Group, Huainan, China.
  • 7 Department of immunology, School of Medicine, Anhui University of Science and Technology, Huainan, China. [email protected].
  • 8 Anhui Occupational Health and Safety Engineering Laboratory, Huainan, China. [email protected].
  • 9 Department of immunology, School of Medicine, Anhui University of Science and Technology, Huainan, China. [email protected].
  • 10 Anhui Occupational Health and Safety Engineering Laboratory, Huainan, China. [email protected].
  • 11 Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, China. [email protected].
  • 12 Department of immunology, School of Medicine, Anhui University of Science and Technology, Huainan, China. [email protected].
  • 13 Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
  • 14 Anhui Occupational Health and Safety Engineering Laboratory, Huainan, China. [email protected].
  • 15 Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, China. [email protected].
  • # Contributed equally.
PMID: 41130939 DOI: 10.1038/s41392-025-02454-x
Abstract

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.

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