A Compound Screen Based on Isogenic hESC‐Derived β Cell Reveals an Inhibitor Targeting ZnT8‐Mediated Zinc Transportation to Protect Pancreatic β Cell from Stress‐Induced Cell Death

Pancreatic β cell loss by cellular stress contributes to diabetes pathogenesis. Nevertheless, the fundamental mechanism of cellular stress regulation remains elusive. Here, it is found that elevated zinc transportation causes excessive cellular stress in pancreatic β cells in diabetes. With gene-edited human embryonic stem cell-derived β cells (SC-β cells) and human primary islets, the results reveal that elevated zinc transportation initiates the integrated stress response (ISR), and ultimately leads to β cell death. By contrary, genetic abolishment of zinc transportation shields β cells from exacerbated endoplasmic reticulum stress (ER stress) and concurrent ISR. To target excessive zinc transportation with a chemical inhibitor, an isogenic SC-β cells based drug-screening platform is established. Surprisingly, independent of its traditional role as protein synthesis inhibitor at a high-dose (10 µm), low-dose (25 nm) anisomycin significantly inhibits zinc transportation and effectively prevents β cell loss. Remarkably, in vivo administration of anisomycin in mice demonstrates protective effects on β cells and prevents type 2 diabetes induced by high-fat diet. Overall, elevated zinc transportation is identified as a crucial driver of β cell loss and low-dose anisomycin as a potential therapeutic molecule for diabetes.

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Publication Details

Journal
Advanced Science
Published
2025-04-07
DOI
https://doi.org/10.1002/advs.202413161
Citations
2
Primary Topic
Pancreatic function and diabetes
Type
article
Field-Weighted Citation Impact
4.01

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article

A Compound Screen Based on Isogenic hESC‐Derived β Cell Reveals an Inhibitor Targeting ZnT8‐Mediated Zinc Transportation to Protect Pancreatic β Cell from Stress‐Induced Cell Death

Wenjun Xu, Ruirui Zhao, Shuangshuang Chen, Minglu Xu et al.
2 citations
Advanced Science
Pancreatic function and diabetes
4.01
article

A Compound Screen Based on Isogenic hESC‐Derived β Cell Reveals an Inhibitor Targeting ZnT8‐Mediated Zinc Transportation to Protect Pancreatic β Cell from Stress‐Induced Cell Death

Wenjun Xu, Ruirui Zhao, Shuangshuang Chen, Minglu Xu, Gaowei Wang, Yunhui Kong, Tinghui Xiao, Weida Li, Yiling Yang, Xiaobo Li, Xuan Wang, Yanfang Liu, Qing He, Meng Guo, Xiangyi Chen, Zhaoyue Wang, Qing Ma, Rui Hu, Yajuan Su, Xushu Wang
article en
2 citations

Abstract

Pancreatic β cell loss by cellular stress contributes to diabetes pathogenesis. Nevertheless, the fundamental mechanism of cellular stress regulation remains elusive. Here, it is found that elevated zinc transportation causes excessive cellular stress in pancreatic β cells in diabetes. With gene-edited human embryonic stem cell-derived β cells (SC-β cells) and human primary islets, the results reveal that elevated zinc transportation initiates the integrated stress response (ISR), and ultimately leads to β cell death. By contrary, genetic abolishment of zinc transportation shields β cells from exacerbated endoplasmic reticulum stress (ER stress) and concurrent ISR. To target excessive zinc transportation with a chemical inhibitor, an isogenic SC-β cells based drug-screening platform is established. Surprisingly, independent of its traditional role as protein synthesis inhibitor at a high-dose (10 µm), low-dose (25 nm) anisomycin significantly inhibits zinc transportation and effectively prevents β cell loss. Remarkably, in vivo administration of anisomycin in mice demonstrates protective effects on β cells and prevents type 2 diabetes induced by high-fat diet. Overall, elevated zinc transportation is identified as a crucial driver of β cell loss and low-dose anisomycin as a potential therapeutic molecule for diabetes.

Advanced ScienceVol. 12(20)
Shanghai University (CN), Second Military Medical University (CN), Changhai Hospital (CN), Shanghai East Hospital (CN), Nanjing University (CN)
National Natural Science Foundation of China, China Postdoctoral Science Foundation, Science and Technology Commission of Shanghai Municipality, Fundamental Research Funds for the Central Universities
Good health and well-being
Openalex Percentile: Top 8%
Pancreatic function and diabetes
4.01
DOIOpen Access PDFOpenAlex
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