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Background <p>Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive respiratory disease characterized by aberrant epithelial remodeling, excessive extracellular matrix (ECM) deposition, and fibroblast activation. Although LKB1-AMPK signaling axis is known to suppress epithelial-to-mesenchymal transition (EMT) and lung fibrosis, the upstream regulatory mechanisms governing this pathway remain unclear. General control non-depressible 5 (GCN5) is a lysine acetyltransferase that modulates protein function and cellular pathways via acetylation, but its contribution to lung fibrosis has not been investigated.</p> Methods <p>To investigate the role of GCN5 in pulmonary fibrosis, we analyzed publicly available transcriptomic datasets from IPF patients. GCN5 expression was validated in lung tissues from IPF patients and mouse fibrosis models (lung-specific TGF-β<sub>1</sub> transgenic and bleomycin-treated mice) using immunohistochemistry. Protein-protein interactions between GCN5 and LKB1 were assessed by co-immunofluorescence in mouse tissues and in vitro translation followed by immunoprecipitation. LKB1 acetylation sites were identified using in silico docking system and functionally validated by site-directed mutagenesis. GCN5 knockdown and overexpression were performed in lung epithelial cells to examine downstream signaling. To evaluate therapeutic potential, GCN5-expressing adenovirus was delivered intratracheally to bleomycin-treated mice.</p> Results <p>Here, we revealed a significantly reduced expression of GCN5 in lung tissues from both patients with IPF and lung fibrosis mouse models. Notably, GCN5 directly bound to liver kinase B1 (LKB1), a master regulator of AMP-activated protein kinase (AMPK), and acetylated LKB1 lysine residues at its C-terminal region. In particular, GCN5-mediated LKB1 acetylation at lysine 431 (K431) enhanced LKB1 kinase activity. GCN5 knockdown in lung epithelial cells reduced LKB1 acetylation at K431, leading to decreased AMPK phosphorylation and subsequent promotion of EMT. Conversely, GCN5 overexpression reversed transforming growth factor-beta–induced profibrotic phenotype. Furthermore, adenovirus-mediated overexpression of GCN5 alleviated fibrosis in bleomycin-treated mice.</p> Conclusions <p>Our findings identify GCN5 as a novel upstream regulator of the LKB1–AMPK signaling in lung epithelial cells. GCN5 deficiency in fibrotic conditions reduces LKB1 acetylation and disrupts epithelial homeostasis, facilitating EMT and fibrosis progression. Restoring GCN5 expression rescues this signaling axis and mitigates fibrosis, highlighting its potential as a therapeutic target of IPF.</p> Graphical Abstract <p></p>

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Deficiency of GCN5 exacerbates pulmonary fibrosis by disrupting the LKB1–AMPK pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Seunghee Byun,
  • Hyunsik Kim,
  • Sun-Ho Lee,
  • Jae-Hwan Kwon,
  • Hyunseung Kim,
  • Myung Hyun Sohn,
  • Hyo Sup Shim,
  • Moo Suk Park,
  • Chun Geun Lee,
  • Jack A. Elias,
  • Jung-Yoon Yoo,
  • Soo-Yeon Park,
  • Ho-Geun Yoon

摘要

Background

Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive respiratory disease characterized by aberrant epithelial remodeling, excessive extracellular matrix (ECM) deposition, and fibroblast activation. Although LKB1-AMPK signaling axis is known to suppress epithelial-to-mesenchymal transition (EMT) and lung fibrosis, the upstream regulatory mechanisms governing this pathway remain unclear. General control non-depressible 5 (GCN5) is a lysine acetyltransferase that modulates protein function and cellular pathways via acetylation, but its contribution to lung fibrosis has not been investigated.

Methods

To investigate the role of GCN5 in pulmonary fibrosis, we analyzed publicly available transcriptomic datasets from IPF patients. GCN5 expression was validated in lung tissues from IPF patients and mouse fibrosis models (lung-specific TGF-β1 transgenic and bleomycin-treated mice) using immunohistochemistry. Protein-protein interactions between GCN5 and LKB1 were assessed by co-immunofluorescence in mouse tissues and in vitro translation followed by immunoprecipitation. LKB1 acetylation sites were identified using in silico docking system and functionally validated by site-directed mutagenesis. GCN5 knockdown and overexpression were performed in lung epithelial cells to examine downstream signaling. To evaluate therapeutic potential, GCN5-expressing adenovirus was delivered intratracheally to bleomycin-treated mice.

Results

Here, we revealed a significantly reduced expression of GCN5 in lung tissues from both patients with IPF and lung fibrosis mouse models. Notably, GCN5 directly bound to liver kinase B1 (LKB1), a master regulator of AMP-activated protein kinase (AMPK), and acetylated LKB1 lysine residues at its C-terminal region. In particular, GCN5-mediated LKB1 acetylation at lysine 431 (K431) enhanced LKB1 kinase activity. GCN5 knockdown in lung epithelial cells reduced LKB1 acetylation at K431, leading to decreased AMPK phosphorylation and subsequent promotion of EMT. Conversely, GCN5 overexpression reversed transforming growth factor-beta–induced profibrotic phenotype. Furthermore, adenovirus-mediated overexpression of GCN5 alleviated fibrosis in bleomycin-treated mice.

Conclusions

Our findings identify GCN5 as a novel upstream regulator of the LKB1–AMPK signaling in lung epithelial cells. GCN5 deficiency in fibrotic conditions reduces LKB1 acetylation and disrupts epithelial homeostasis, facilitating EMT and fibrosis progression. Restoring GCN5 expression rescues this signaling axis and mitigates fibrosis, highlighting its potential as a therapeutic target of IPF.

Graphical Abstract