1. Academic Validation
  2. Cadmium induces liver dysfunction and ferroptosis through the endoplasmic stress-ferritinophagy axis

Cadmium induces liver dysfunction and ferroptosis through the endoplasmic stress-ferritinophagy axis

  • Ecotoxicol Environ Saf. 2022 Sep 29;245:114123. doi: 10.1016/j.ecoenv.2022.114123.
Zhaoqi He 1 Peng Shen 1 Lianjun Feng 1 Haoyang Hao 1 Yuhong He 1 Guyue Fan 1 Zhuoyu Liu 1 Kun Zhu 1 Yiqi Wang 1 Naisheng Zhang 1 Xiaoyu Hu 1 Yunhe Fu 1 Jiacheng Wu 2
Affiliations

Affiliations

  • 1 Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province 130062, People Republic of China.
  • 2 Department of Hepatolibiary Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin Province 130062, People Republic of China. Electronic address: wujiacheng2005@jlu.edu.cn.
Abstract

Cadmium (Cd) is a type of high-risk heavy metal that can damage organs such as the liver, but its mechanism is not yet clear. Ferroptosis is a newly discovered mode of regulatory cell death. We explored whether Ferroptosis is involved in Cd-induced liver damage and the underlying mechanism. Our research showed that Cd induced liver damage by inducing Ferroptosis, and the use of Ferroptosis inhibitors reduced the degree of liver damage. Moreover, the occurrence of Ferroptosis was accompanied by the activation of the PERK-eIF2α-ATF4-CHOP signaling pathway, and inhibiting endoplasmic reticulum (ER) stress reduced Ferroptosis demonstrating that Ferroptosis induced by Cd is dependent on ER stress. In addition, chloroquine, a common Autophagy Inhibitor, mitigated Ferroptosis caused by Cd exposure. Then, the iron chelator deferoxamine reduced Cd-induced lipid peroxidation and cell death, demonstrating that the iron regulation disorder caused by ferritin phagocytosis contributes to the Cd-induced Ferroptosis. In conclusion, our results show that Cd-induced liver toxicity is accompanied by Ferroptosis, which contributes to Cd inducing oxidative stress to trigger Autophagy and ER stress to promote the process of Ferroptosis.

Keywords

Autophagy; Cadmium; Endoplasmic reticulum stress; Ferroptosis; Liver.

Figures
Products