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The lack of a suitable human model in WS has impeded progress in the development of new treatments. Here, human pluripotent stem cell derived pancreatic islets (SC-islets) harboring <jats:italic>WFS1<\/jats:italic> deficiency and mouse model of \u03b2 cell specific <jats:italic>Wfs1<\/jats:italic> knockout were applied to model \u03b2-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS \u03b2-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. <jats:italic>WFS1<\/jats:italic> deficiency disrupted \u03b2-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to \u03b2-cell failure. Notably, further investigation of the stress trajectory identified activated integrated stress response (ISR) as a crucial mechanism underlying WS \u03b2-cell failure, characterized by aberrant eIF2 signaling in <jats:italic>WFS1<\/jats:italic>-deficient SC-islets, along with elevated expression of genes in regulating stress granule formation. Significantly, we demonstrated that ISRIB, an ISR inhibitor, efficiently reversed \u03b2-cell failure in <jats:italic>WFS1<\/jats:italic>-deficient SC-islets. We further validated therapeutic efficacy in vivo with \u03b2-cell specific <jats:italic>Wfs1<\/jats:italic> knockout mice. Altogether, our study provides novel insights into WS pathogenesis and offers a strategy targeting ISR to treat WS diabetes.<\/jats:p>","DOI":"10.1038\/s41418-024-01258-w","type":"journal-article","created":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T14:02:33Z","timestamp":1707228153000},"page":"322-334","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["ISR inhibition reverses pancreatic \u03b2-cell failure in Wolfram syndrome models"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3152-6649","authenticated-orcid":false,"given":"Rui","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xushu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengting","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minglu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongrong","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3798-7104","authenticated-orcid":false,"given":"Zhen-Ning","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6578-6321","authenticated-orcid":false,"given":"Weida","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,6]]},"reference":[{"key":"1258_CR1","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1002\/humu.1110","volume":"17","author":"F Khanim","year":"2001","unstructured":"Khanim F, Kirk J, Latif F, Barrett TG. 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