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This abnormal sympathetic nervous signaling may disrupt the balance of the neuroendocrine\u2010immune network and contribute to the development of T1D, although its underlying molecular mechanisms are still elusive. Here, single\u2010cell omics and whole\u2010tissue immunostaining reveal a decrease in pancreatic sympathetic nerve density in T1D patients and T1D mouse models. Surgical and chemical desensitization of the sympathetic nervous system exacerbates T1D, while macrophage depletion mitigates this effect. Mechanistically, diminished norepinephrine (NE) release impairs \u03b22\u2010adrenergic receptor (\u03b22\u2010AR)\u2010PKA\u2010CREB1 signaling in islet macrophages, leading to downregulation of the adaptor caspase recruitment domain family member 9 (CARD9). Loss of CARD9 decreases SLC6A8\u2010mediated creatine uptake, shifts macrophages toward a pro\u2010inflammatory phenotype, and promotes sympathetic axon ferroptosis driven by decreased neurotrophic factor and anti\u2010inflammatory factor release. Conversely, \u03b22\u2010AR agonist formoterol restores PKA\u2010CREB1\u2010CARD9 activation, preserves creatine metabolism, and maintains anti\u2010inflammatory macrophage polarization. These findings define a novel sympathetic\u2010macrophage\u2010creatine metabolic axis governed by CARD9 that links neural signals to immune and metabolic regulation in T1D, highlighting neuroimmune interactions as targets for therapies.<\/jats:p>","DOI":"10.1002\/advs.202507543","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T04:37:02Z","timestamp":1763354222000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CARD9 Conveys Pancreatic Islet Sympathetic Nervous \u03b22 Signals to Reshape Macrophage Creatine Metabolism in Type 1 Diabetes"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6253-7585","authenticated-orcid":false,"given":"Huimin","family":"Yuan","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Pharmacy Tongji Medical College Huazhong University of Science and Technology  Wuhan 430000 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