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  3. Melatonin protects against cadmium-induced endoplasmic reticulum stress and ferroptosis through activating Nrf2/HO-1 signaling pathway in mice lung

Melatonin protects against cadmium-induced endoplasmic reticulum stress and ferroptosis through activating Nrf2/HO-1 signaling pathway in mice lung

  • Food Chem Toxicol. 2025 Apr:198:115324. doi: 10.1016/j.fct.2025.115324.
Ziyang Huang 1,  Ruijia Xu 2,  Zhongjun Wan 3,  Chao Liu 2,  Jinquan Li 2,  Jun He 4,  Li Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, School of Life Science, Hubei University, Wuhan, 430070, China; School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China.
  • 2 School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China.
  • 3 State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, School of Life Science, Hubei University, Wuhan, 430070, China.
  • 4 School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China; Institute of Forensic Medicine, Wuhan University School of Medicine, Wuhan, 430072, China. Electronic address: hojon@126.com.
  • 5 State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, School of Life Science, Hubei University, Wuhan, 430070, China. Electronic address: lily@hubu.edu.cn.
PMID: 39954982 DOI: 10.1016/j.fct.2025.115324
Abstract

Cadmium (Cd) is a prevalent heavy metal pollutant known to cause lung damage. However, the mechanisms underlying Cd-induced lung injury and the associated therapeutic strategies remain unclear. By establishing Cd-induced lung damage models both in vivo and in vitro, we observed that Cd inhibited the Nrf2/HO-1 signaling pathway, disrupted the redox balance in lung tissue, accelerated endoplasmic reticulum (ER) stress, and promoted Ferroptosis, ultimately leading to lung injury. Melatonin (Mel), a potent Reactive Oxygen Species (ROS) inhibitor with high antioxidative efficacy, mitigated the increasing in ROS and the decreasing in superoxide dismutase levels induced by Cd, as well as the upregulation of PERK-eIF2α-ATF4 signaling associated with ER stress, through the activation of the Nrf2/HO-1 signaling pathway. Furthermore, Mel administration not only prevented Cd-induced iron overload but also reduced lipid peroxidation levels, thereby improving mitochondrial morphological alterations. Collectively, our results demonstrated that Mel treatment alleviated Cd-induced lung injury by inhibiting oxidative stress, which in turn ameliorated ER stress and Ferroptosis through the activation of the Nrf2/HO-1 pathway.

Keywords

Cadmium; Endoplasmic reticulum stress; Ferroptosis; Lung injury; Melatonin.

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