Zinc transporter ZIP7 is a novel determinant of ferroptosis
Abstract
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>SLC39A7</jats:italic>,
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 <jats:italic>HERPUD1</jats:italic> and <jats:italic>ATF3</jats:italic>.
Importantly, the knockdown of <jats:italic>HERPUD1</jats:italic> 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.</jats:p>
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https://hdl.handle.net/10161/22377Published Version (Please cite this version)
10.1038/s41419-021-03482-5Publication Info
Chen, Po-Han; Wu, Jianli; Xu, Yitong; Ding, Chien-Kuang Cornelia; Mestre, Alexander
A; Lin, Chao-Chieh; ... Chi, Jen-Tsan (2021). Zinc transporter ZIP7 is a novel determinant of ferroptosis. Cell Death & Disease, 12(2). 10.1038/s41419-021-03482-5. Retrieved from https://hdl.handle.net/10161/22377.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Jen-Tsan Ashley Chi
Professor in Molecular Genetics and Mirobiology
We are using functional genomic approaches to investigate the nutrient signaling and
stress adaptations of cancer cells when exposed to various nutrient deprivations and
microenvironmental stress conditions. Recently, we focus on two areas. First, we are
elucidating the genetic determinants and disease relevance of ferroptosis, a newly
recognized form of cell death. Second, we have identified the mammalian stringent
response pathway which is highly similar to bacterial stringent response, but

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