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  3. A translational in vitro to in vivo study on chronic arsenic exposure induced pulmonary ferroptosis and multi-omics analysis of gut-lung axis correlation

A translational in vitro to in vivo study on chronic arsenic exposure induced pulmonary ferroptosis and multi-omics analysis of gut-lung axis correlation

  • J Hazard Mater. 2025 Jun 23:495:139049. doi: 10.1016/j.jhazmat.2025.139049.
Sanaullah Sajid 1,  Xu Chen 2,  Yanqin Sun 3,  Junjie Luo 4,  Bin Zhang 4,  Linkang Chen 4,  Jieliang Huang 4,  Chengze Lai 1,  Yongchun Chen 5,  Lianxian Guo 6
Affiliations

Affiliations

  • 1 Dongguan Key Laboratory of Public Health Laboratory Science, School of Public Health, Guangdong Medical University, Dongguan 523808, China; Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China.
  • 2 Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225001, China.
  • 3 Department of Pathology, Guangdong Medical University, Dongguan 523808, China.
  • 4 Dongguan Key Laboratory of Public Health Laboratory Science, School of Public Health, Guangdong Medical University, Dongguan 523808, China.
  • 5 Department of Hematology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225001, China. Electronic address: cyc052149@163.com.
  • 6 Dongguan Key Laboratory of Public Health Laboratory Science, School of Public Health, Guangdong Medical University, Dongguan 523808, China; Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China. Electronic address: glx525@gdmu.edu.cn.
PMID: 40614423 DOI: 10.1016/j.jhazmat.2025.139049
Abstract

Background: Chronic arsenic exposure is a global health concern linked to pulmonary diseases like fibrosis. However, its precise molecular mechanisms remain unclear. This study explored the effects of chronic arsenic exposure on a murine model (via diet) and BEAS-2B cells, focusing on oxidative stress, lipid peroxidation, mitochondrial dysfunction, and ferroptosis-mediated cell death.

Methods: BEAS-2B cells were exposed to 1 μmol/L NaAsO₂ for 30 passages. Oxidative stress was assessed via ROS quantification, GSH depletion, and T-SOD activity. Lipid peroxidation was measured using BODIPY fluorescence and MDA levels. Mitochondrial dysfunction was determined by mtROS imaging and JC-1 staining. Ferroptosis was analyzed through GPX4 expression and TEM-based mitochondrial integrity. A 14-month murine model evaluated histopathology, metabolomic dysregulation, and gut-lung axis crosstalk.

Results: Arsenic exposure significantly increased ROS, depleted GSH, and reduced T-SOD activity. Lipid peroxidation and mitochondrial dysfunction were evident, with more than 60 % decline in GPX4. Murine lung histology showed alveolar thickening, inflammatory infiltration, and elevated IL-6, TNF-α, and VEGF. Metabolomic analysis revealed disrupted lipid metabolism, correlating with Ferroptosis markers (Acetyl-carnitine, L-Acetylcarnitine).

Conclusions: This was the first study to demonstrate Ferroptosis as a key mechanism in arsenic-induced lung epithelial damage using a 14-month murine model and a 30-passage cellular model. We further demonstrated that Ferroptosis induced by chronic exposure becomes functionally irreversible, as Ferroptosis inhibition by Ferrostatin-1 failed to rescue GPX4 expression, unlike prior acute exposure models.

Keywords

Arsenic toxicity; Ferroptosis; Lipid peroxidation; Mitochondrial dysfunction; Oxidative stress.

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