1. Academic Validation
  2. Zinc transporter ZIP7 is a novel determinant of ferroptosis

Zinc transporter ZIP7 is a novel determinant of ferroptosis

  • Cell Death Dis. 2021 Feb 19;12(2):198. doi: 10.1038/s41419-021-03482-5.
Po-Han Chen  # 1 2 Jianli Wu  # 1 2 Yitong Xu 1 2 Chien-Kuang Cornelia Ding 1 2 Alexander A Mestre 1 2 3 Chao-Chieh Lin 1 2 Wen-Hsuan Yang 1 2 3 Jen-Tsan Chi 4 5
Affiliations

Affiliations

  • 1 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27708, USA.
  • 2 Duke Center for Genomic and Computational Biology, Duke University, Durham, NC, 27708, USA.
  • 3 Department of Biochemistry, Duke University Medical Center, Durham, NC, 27708, USA.
  • 4 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, 27708, USA. jentsan.chi@duke.edu.
  • 5 Duke Center for Genomic and Computational Biology, Duke University, Durham, NC, 27708, USA. jentsan.chi@duke.edu.
  • # Contributed equally.
Abstract

Ferroptosis is a newly described form of regulated cell death triggered by oxidative stresses and characterized by extensive lipid peroxidation and membrane damages. The name of Ferroptosis indicates that the ferroptotic death process depends on iron, but not other metals, as one of its canonical features. Here, we reported that zinc is also essential for Ferroptosis in breast and renal Cancer cells. Zinc chelator suppressed Ferroptosis, and zinc addition promoted Ferroptosis, even during iron chelation. By interrogating zinc-related genes in a genome-wide RNAi screen of Ferroptosis, we identified SLC39A7, encoding ZIP7 that controls zinc transport from endoplasmic reticulum (ER) to cytosol, as a novel genetic determinant of Ferroptosis. Genetic and chemical inhibition of the ZIP7 protected cells against Ferroptosis, and the Ferroptosis protection upon ZIP7 knockdown can be abolished by zinc supplementation. We found that the genetic and chemical inhibition of ZIP7 triggered ER stresses, including the induction of the expression of HERPUD1 and ATF3. Importantly, the knockdown of HERPUD1 abolished the Ferroptosis protection phenotypes of ZIP7 inhibition. Together, we have uncovered an unexpected role of ZIP7 in Ferroptosis by maintaining ER homeostasis. These findings may have therapeutic implications for human diseases involving Ferroptosis and zinc dysregulations.

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