Inhibition of the 4-hydroxynonenal-regulated JNK/c-Jun pathway improves bleomycin-induced lung fibrosis

  • Biomed J. 2025 Oct 9:100916. doi: 10.1016/j.bj.2025.100916.
Chen-Chi Liu  1 ,  Jiun-Han Lin  2 ,  Tien-Wei Hsu  2 ,  Chien-Ying Wang  3 ,  Han-Shui Hsu  4
Affiliations
  • 1. Surgical Intensive Care Unit, Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
  • 2. Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 3. Surgical Intensive Care Unit, Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Exercise and Health Sciences, University of Taipei, Taipei, Taiwan.
  • 4. Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: [email protected].
PMID: 41076274 DOI: 10.1016/j.bj.2025.100916
Abstract

Background: Lipid peroxidation and 4-hydroxynonenal (4-HNE) contribute to oxidative stress-related tissue damage, but their roles in pulmonary fibrosis remain unclear. We examined their involvement in bleomycin-induced pulmonary fibrosis.

Materials and methods: Lung fibrosis model mice were used to assess Collagen deposition, lipid peroxidation markers, and oxidative stress. Ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine (DFO) were administered to the mice. In vitro, murine lung epithelial (MLE-12) cells were treated with bleomycin, with or without lipid peroxidation inhibitors, and analyzed for oxidative stress and Apoptosis. 4-HNE expression in idiopathic pulmonary fibrosis lung tissues was assessed using immunohistochemistry.

Results: Bleomycin increased deposition of Collagen and levels of 4-HNE and malondialdehyde levels while decreasing the glutathione/glutathione disulfide ratio. Fer-1 and DFO improved pulmonary function, reduced fibrosis, and restored the glutathione/glutathione disulfide ratio. In vitro, lipid peroxidation inhibition suppressed bleomycin-induced cell death and oxidative stress. Direct 4-HNE treatment induced Apoptosis and lipid peroxidation, implicating 4-HNE in epithelial injury. 4-HNE upregulation was linked to increased transforming growth factor-β expression via c-Jun amino-terminal kinase/c-Jun signaling. Fer-1 and DFO mitigated these effects. Human idiopathic pulmonary fibrosis tissues exhibited elevated 4-HNE, correlating with fibrosis severity.

Conclusions: Lipid peroxidation and 4-HNE play key roles in pulmonary fibrosis progression. Their regulation of transforming growth factor-β expression suggests targeting lipid peroxidation as a potential therapeutic strategy.

Keywords
4-HNE; JNK; TGF-β; lipid peroxidation; pulmonary fibrosis.
Products