biostudies-literatureHu RNational Natural Science Foundation of China (National Science Foundation of China)Natural Science Foundation of Shanghai (Natural Science Foundation of Shanghai Municipality)322-334https://www.ebi.ac.uk/biostudies/studies/S-EPMC10923889biostudies-literatureUnknown31(3)Pancreatic β-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). 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 WFS1 deficiency and mouse model of β cell specific Wfs1 knockout were applied to model β-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS β-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted β-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to β-cell failure. Notably, further investigation of tCell death and differentiationISR inhibition reverses pancreatic β-cell failure in Wolfram syndrome models.PMC10923889319707518197107832122030323708558217116621ZR145240032170740Xu MShao LLe RLi WSu QDai PGao YGong MChen XWang XHu RWang ZZhang ZNfalseISR inhibition reverses pancreatic β-cell failure in Wolfram syndrome models.Pancreatic β-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). 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 WFS1 deficiency and mouse model of β cell specific Wfs1 knockout were applied to model β-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS β-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted β-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to β-cell failure. Notably, further investigation of t2024-01-01T00:00:00Z2024 Mar2026-07-15T11:57:42.108Z2026-07-04T03:12:03.781ZS-EPMC109238893832121410.1038/s41418-024-01258-w