Comments on ‘BAF60a-dependent chromatin remodeling preserves β-cell function and contributes to the therapeutic benefits of GLP-1R agonists’

Type 2 diabetes (T2D) is a highly prevalent metabolic disease characterized by impaired glucose-stimulated insulin secretion (GSIS) and progressive failure of pancreatic -cell.However, the underlying molecular mechanisms governing -cell dysfunction during the course of T2D remain incompletely understood, and current therapeutic strategies show limited and heterogeneous benefits.Maintaining -cell identity and functional plasticity under metabolic stress is essential for glucose homeostasis.Accumulating evidence indicates that epigenetic remodeling is a central driver of -cell adaptation and deterioration (Kim et al., 2020;Wang et al., 2022).Among epigenetic regulators, ATPdependent SWI/SNF complexes have emerged as key determinants of -cell transcriptional competence.However, whether individual SWI/SNF subunits act as metabolic sensors in -cells is still unclear.In our recent work (Qiu et al., 2025), we performed transposase-accessible chromatin using sequencing (ATAC-Seq) analysis of human and mouse diabetic -cells and identified widespread alterations in chromatin accessibility, particularly at distal enhancer-like regions that regulate insulin secretion and glucose metabolism, consistent with previous reports (Rai et al., 2020).This enhancercentered remodeling prompted us to search for upstream chromatin regulators, and through integrated multi-omics coupled with functional screening, we identified BAF60a as a key SWI/SNF subunit required for maintaining -cell GSIS under metabolic stress.Lipotoxic and inflammatory stimuli markedly reduced BAF60a expression, and -cell-specific deletion of BAF60a impaired insulin secretion and decreased the expression of -cell identity genes, whereas restoration of BAF60a expression rescued these defects.Mechanistically, BAF60a cooperates with the -cell transcription