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Nevertheless, the fundamental mechanism of cellular stress regulation remains elusive. Here, it is found that elevated zinc transportation causes excessive cellular stress in pancreatic \u03b2 cells in diabetes. With gene\u2010edited human embryonic stem cell\u2010derived \u03b2 cells (SC\u2010\u03b2 cells) and human primary islets, the results reveal that elevated zinc transportation initiates the integrated stress response (ISR), and ultimately leads to \u03b2 cell death. By contrary, genetic abolishment of zinc transportation shields \u03b2 cells from exacerbated endoplasmic reticulum stress (ER stress) and concurrent ISR. To target excessive zinc transportation with a chemical inhibitor, an isogenic SC\u2010\u03b2 cells based drug\u2010screening platform is established. Surprisingly, independent of its traditional role as protein synthesis inhibitor at a high\u2010dose (10 \u00b5\n                    <jats:sc>m<\/jats:sc>\n                    ), low\u2010dose (25\u00a0n\n                    <jats:sc>m<\/jats:sc>\n                    ) anisomycin significantly inhibits zinc transportation and effectively prevents \u03b2 cell loss. Remarkably, in vivo administration of anisomycin in mice demonstrates protective effects on \u03b2 cells and prevents type 2 diabetes induced by high\u2010fat diet. Overall, elevated zinc transportation is identified as a crucial driver of \u03b2 cell loss and low\u2010dose anisomycin as a potential therapeutic molecule for diabetes.\n                  <\/jats:p>","DOI":"10.1002\/advs.202413161","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T18:27:12Z","timestamp":1744050432000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Compound Screen Based on Isogenic hESC\u2010Derived \u03b2 Cell Reveals an Inhibitor Targeting ZnT8\u2010Mediated Zinc Transportation to Protect Pancreatic \u03b2 Cell from Stress\u2010Induced Cell Death"],"prefix":"10.1002","volume":"12","author":[{"given":"Rui","family":"Hu","sequence":"first","affiliation":[{"name":"Institute for Regenerative Medicine State Key Laboratory of Cardiology and Medical Innovation Center Shanghai East Hospital Frontier Science Center for Stem Cell Research Shanghai Key Laboratory of 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