2. Academic Validation
  3. Poly-l-arginine promotes ferroptosis in asthmatic airway epithelial cells by modulating PBX1/GABARAPL1 axis

Poly-l-arginine promotes ferroptosis in asthmatic airway epithelial cells by modulating PBX1/GABARAPL1 axis

  • Int J Biol Macromol. 2025 Jan:286:138478. doi: 10.1016/j.ijbiomac.2024.138478.
Min Pan 1,  Ling Zhang 1,  Shuang Chang 1,  Xueqin Jiang 2,  Jiapan Shen 1,  Xiaoxia Feng 3,  Fangzhou Xu 2,  Xiaojun Zha 4,  Xu Chen 5,  Xiaoyun Fan 6
Affiliations

Affiliations

  • 1 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China.
  • 2 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China; Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, China.
  • 3 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China.
  • 4 Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
  • 5 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China. Electronic address: chenxu9s@126.com.
  • 6 Department of Geriatric Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei, China; Anhui Geriatric Institute, Hefei, China; Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, China. Electronic address: 13956988552@126.com.
PMID: 39645127 DOI: 10.1016/j.ijbiomac.2024.138478
Abstract

Eosinophils play a featured role among inflammatory cells participating in the onset and development of asthma. Activated eosinophils release several cytotoxic granular proteins, such as major basic protein (MBP), posing a significant threat to airway epithelium. Ferroptosis, a novel form of cell death, is gaining recognition for its involvement in asthma pathogenesis, though the specific mechanisms remain largely unknown. Herein, we revealed that poly-l-arginine (PLA), an MBP mimic, induced Ferroptosis in airway epithelium by downregulating γ-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1). Reduced GABARAPL1 expression was further confirmed in ovalbumin (OVA)-induced asthma mice and PLA-treated human airway organoids (hAOs). Mechanistically, PLA activated mechanistic target of rapamycin complex 1 (mTORC1) signaling, inhibiting pre-B-cell leukemia transcription factor 1 (PBX1), which in turn leads to transcriptional downregulation of GABARAPL1. Furthermore, MBP extracted from eosinophils, similar to PLA, induced Ferroptosis in airway epithelial cells, as well as modulating mTORC1/PBX1/GABARAPL1 pathway. Finally, Ferrostatin-1 treatment or GABARAPL1 overexpression alleviated Ferroptosis and airway inflammation in asthmatic mice. Overall, our findings highlight the cell communication between eosinophils and airway epithelial cells. MBP modulates the mTORC1/PBX1/GABARAPL1 axis, thereby serving as a significant contributor to Ferroptosis in airway epithelium and airway inflammation. This suggests that suppressing Ferroptosis in airway epithelium or targeting eosinophils and MBP could lead to novel therapeutic strategies for asthma management.

Keywords

Airway inflammation; Asthma; Eosinophil; Ferroptosis; Poly-l-arginine; γ-aminobutyric acid receptor-associated protein-like.

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