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

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 µ m ), low‐dose (25 n m ) 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.