2. Academic Validation
  3. Single-cell perturbations decipher ribosomal stress-surveillance regulators in type 2 diabetes

Single-cell perturbations decipher ribosomal stress-surveillance regulators in type 2 diabetes

  • Nat Metab. 2026 Jan;8(1):139-158. doi: 10.1038/s42255-025-01407-6.
Jingminjie Nan # 1,  Xianglong He # 1,  Xiaoping Liu # 2,  Jianrong Ran 1,  Jiahuan Chen 1,  Pengxiao Li 3,  Dongxue Liu 2,  Yanan Sun 2,  Aijing Shan 2,  Xiuli Jiang 2,  Jing Xie 4,  Weiqing Wang 2,  Guang Ning 2,  Yanan Cao 5 6 7
Affiliations

Affiliations

  • 1 Ruijin Yangtze River Delta Health Institute, Wuxi Branch of Ruijin Hospital, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 National Research Center for Translational Medicine, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Ruijin Yangtze River Delta Health Institute, Wuxi Branch of Ruijin Hospital, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 6 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 7 National Research Center for Translational Medicine, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41482566 DOI: 10.1038/s42255-025-01407-6
Abstract

Systemic characterization of genes and pathways underlying the genetic architecture of type 2 diabetes (T2D) requires scalable functional genomics approaches. Molecular readouts from CRISPR perturbations can effectively uncover the mechanistic effects of underexplored genes. Here we performed single-cell RNA Sequencing on pooled CRISPR screens (Perturb-seq) of 61 T2D-associated genes and 40 ribosome-associated quality control (RQC) genes in human pancreatic β cells (EndoC-βH1) for investigations of Insulin production and T2D pathology. We identified 21 functional genes, including the uncharacterized KLHL42 and ZZEF1. Findings from global and β cell-specific knockout male mice, islet organoids and human islets reveal that ZZEF1 is a regulator of Insulin synthesis and β cell stress through ribosomal stress-surveillance pathways in working and stress status-defined β cell subtypes. ZZEF1 deficiency impairs β cell function by inhibiting the RQC sensor EDF1, which could be improved by azoramide and ISRIB treatments. These Perturb-seq analyses and identification of functional RQC-related genes can provide potential therapeutic targets for T2D.

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