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Zinc accumulation-induced integrated stress response triggers β-cell identity loss

Qing Ma^1,† , Wenjun Xu^1,† , Xuan Wang^1,† , Haoyu Nie^1,† , Yukun Gao¹ , Rui Hu¹ , Zhihao Yang¹ , Xushu Wang¹ , Ta Na² , Xiangyi Chen¹ , Zhaoyue Wang¹ , Minglu Xu¹ , Li Shao³ , Meng Guo² , Yanfang Liu² , Rongrong Le¹ , Shaorong Gao^1,* , Weida Li^1,4,*

¹Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
²Department of Pathology, Changhai Hospital, Navy Medical University, Shanghai, China
³Department of VIP Clinic, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
⁴Reg-Verse Therapeutics (Shanghai) Co. Ltd., Shanghai, China
^†These authors contributed equally: Qing Ma, Wenjun Xu, Xuan Wang, Haoyu Nie
* Correspondence: Shaorong Gao(gaoshaorong@tongji.edu.cn)Weida Li(weidali@tongji.edu.cn)

Pancreatic β-cell identity loss is increasingly recognized as a critical pathogenic contributor to β-cell failure in type 2 diabetes (T2D), but the specific mechanism remains to be characterized. In this study, we demonstrate that zinc accumulation contributes to β-cell identity loss during diabetes progression in both human and mouse islets. Using a model of human embryonic stem cell-derived islets (SC-islets), we reveal that accumulated zinc triggers the integrated stress response (ISR), with elevated ATF4 expression in SC-β cells. This, in turn, initiates expression of the α cell-specific transcription factor ARX, resulting in the conversion of β cells to α cells, thus forming a zinc-ATF4-ARX regulatory axis. Like primary β cells, SC-β cells also undergo identity loss after transplantation into diabetic animals, which can be prevented by an ISR inhibitor, resulting in improved glycemic control. Furthermore, both genetic depletion and chemical inhibition of zinc accumulation effectively safeguard SC-β cells from identity loss and enhance their efficacy in diabetic animals. Our study thus reveals a pathogenic mechanism in which zinc accumulation induces β-cell identity loss through lineage-tracing approaches and proposes a protective strategy to counteract this process.

https://doi.org/10.1038/s41422-026-01222-y

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