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
  • 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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