Nature子刊：上海交通大学曹亚南团队通过单细胞扰动，解码2型糖尿病中核糖体应激监控新机制和靶点

Core Viewpoint - The research highlights the need for high-throughput, high-resolution functional genomics platforms based on human normal cells to systematically reveal the pathogenic mechanisms of complex diseases like Type 2 Diabetes (T2D) and provide new paradigms for therapeutic target discovery [3]. Group 1: Research Findings - A study published in Nature Metabolism utilized single-cell perturbation sequencing to decode the functions of genes related to T2D and insulin production in human pancreatic β cells, identifying the previously unknown gene ZZEF1 [4]. - The research team identified 21 significant functional genes affecting β cells, including known genes like ABCC8 and PCSK1, as well as the novel ZZEF1 gene [6]. - ZZEF1's perturbation was found to impact pathways related to β cell homeostasis, MAPK/JNK stress response, protein secretion, and endoplasmic reticulum stress response, indicating its potential as a key regulatory factor [7]. Group 2: Mechanistic Insights - The study constructed cell-specific knockout mouse models to validate ZZEF1's function, revealing that ZZEF1 knockout mice exhibited impaired glucose tolerance and reduced insulin secretion under high-fat diet conditions [8]. - ZZEF1 deficiency led to decreased insulin protein levels without significant transcriptional reduction, suggesting issues in insulin translation or post-translational modifications [8]. - The research categorized β cells into four functional subgroups based on their activity and stress levels, demonstrating that ZZEF1 deficiency shifts these subgroups towards a high-stress state [8]. Group 3: Therapeutic Implications - The research tested various intervention strategies, including the use of adeno-associated virus (AAV) to restore EDF1 expression, which significantly improved insulin secretion in ZZEF1 knockout mice [10]. - The small molecule drug Azoramide was shown to enhance the degradation of misfolded proteins, improving glucose tolerance and partially restoring insulin secretion function in ZZEF1 knockout mice [10]. - These findings suggest that targeting ribosomal stress, protein homeostasis, and the elimination of misfolded protein accumulation could be new strategies for protecting β cells and treating T2D [10]. Group 4: Conclusion - The study demonstrates the advantages of single-cell functional genomics in the genetic analysis of complex diseases, establishing a new paradigm for systematically elucidating the molecular mechanisms and targets of T2D [12].