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

Haq, N. A.; Toczyska, K. W.; Islam, A.; Olaniru, O. E.; Lei, Y.; Hu, M.; Zhao, M.; Müller, R.; Mirza, M. K. M.; Fine, N. H. F.; Hodson, D. J.; Persaud, S. J.; Beck-Sickinger, A. G.; Pearson, J.; Bewick, G. A.

doi:10.64898/2026.07.03.736290

bioRxiv · 10.64898/2026.07.03.736290

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

Haq, N. A.·Toczyska, K. W.·Islam, A.·Olaniru, O. E.·Lei, Y.·Hu, M.·Zhao, M.·Müller, R.·Mirza, M. K. M.·Fine, N. H. F.·Hodson, D. J.·Persaud, S. J.·Beck-Sickinger, A. G.·Pearson, J.·Bewick, G. A.

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Abstract

Type 1 diabetes (T1D) involves immune-mediated destruction of pancreatic {beta}-cells, yet current disease-modifying therapies mainly target immunity without enhancing {beta}-cell resilience. We show selective neuropeptide Y4 receptor (Y4R) agonism protects {beta}-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 {beta}-cells. Selective Y4R agonism was non-toxic and did not impair islet network integrity, Ca{superscript 2} 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 {beta}-cell loss whilst sustaining insulin release and promoting proliferation in both mouse and human islets. Bulk RNA-seq revealed a coordinated {beta}-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 {beta}-cell-centric therapeutic target coupling intrinsic resilience with local immune modulation, offering a complementary approach for {beta}-cell preservation in T1D and islet replacement therapies. Graphical abstractThe selective Y4 receptor agonist K22 binds {beta}-cell-enriched NPY4R in mouse and human islets, activates a {beta}-cell resilience programme that preserves insulin secretion under inflammatory and metabolic stress, and simultaneously dampens islet chemokine output, thereby limiting innate and adaptive immune-cell recruitment and delaying autoimmune diabetes onset. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/736290v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@7efd48org.highwire.dtl.DTLVardef@1268860org.highwire.dtl.DTLVardef@c38a81org.highwire.dtl.DTLVardef@1ba3e6c_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Haq, N. A., Toczyska, K. W., Islam, A., Olaniru, O. E., Lei, Y., Hu, M., Zhao, M., Müller, R., Mirza, M. K. M., Fine, N. H. F., Hodson, D. J., Persaud, S. J., Beck-Sickinger, A. G., Pearson, J., Bewick, G. A.. 2026-07-04. Neuropeptide Y4 receptor activation delays autoimmune diabetes by reprogramming β-cell stress and immune tolerance. https://doi.org/10.64898/2026.07.03.736290

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