Neuropeptide Y4 receptor activation delays autoimmune diabetes by reprogramming β-cell stress and immune tolerance

Type 1 diabetes (T1D) involves immune-mediated destruction of pancreatic β-cells, yet current disease-modifying therapies mainly target immunity without enhancing β-cell resilience. We show selective neuropeptide Y4 receptor (Y4R) agonism protects β-cells while reshaping islet immunity across T1D models. Multi-modal localisation using cell sorting, qPCR, RNAscope and fluorescent ligand competition demonstrated predominant Y4R expression and functional accessibility on mouse and human β-cells. Selective Y4R agonism was non-toxic and did not impair islet network integrity, Ca²⁺ dynamics, glucose-stimulated insulin secretion or systemic glucose tolerance. Y4R activation conferred cytoprotection against inflammatory cytokines, streptozotocin, lipotoxicity and ER stress, reducing caspase-3/7 activation and β-cell loss whilst sustaining insulin release and promoting proliferation in both mouse and human islets. Bulk RNA-seq revealed a coordinated β-cell resilience programme characterised by reinforced identity and insulin processing, KEAP1-NFE2L2-driven antioxidative and proteostatic activation, and suppression of EIF2 signalling and associated biosynthetic and ER stress pathways. Concurrently, Y4R agonism dampened pathogenic chemokine and cytokine networks, including CXCL10, CCL3/4/7 and IL-6, while preserving IL-2 and Foxp3 signals, thereby limiting CD8⁺ T cell, CD4⁺ T cell and macrophage chemotaxis toward cytokine-stressed islets. Reduced immune-cell recruitment was conserved in a fully human immune-islet system, where Y4R activation significantly attenuated IL-2-activated human PBMC migration and invasion toward cytokine-stressed human islets. In a stringent NY8.3 CD8⁺ T cell adoptive-transfer model, systemic Y4R agonism significantly delayed diabetes onset. These data position Y4R as a β-cell-centric therapeutic target coupling intrinsic resilience with local immune modulation, offering a complementary approach for β-cell preservation in T1D and islet replacement therapies.