Thymosin Alpha‐1 Provides Direct Neuroprotection by Engaging the Orexin Receptor HCRTR1 to Suppress Neuronal Necroptosis

Communication between the immune system and the brain is critical for neuronal health, yet the molecular signals that mediate this crosstalk are not fully understood. Here, we uncover an unexpected and direct neuroprotective axis linking the thymus to the central nervous system (CNS). We show that the thymus-derived peptide Thymosin alpha-1 (Tα1) functions as a non-canonical ligand for the Hypocretin (Orexin) Receptor 1 (HCRTR1), a classical neuropeptide receptor on neurons. This engagement shields neurons from cell death by suppressing the activity of Receptor-Interacting Protein Kinase 3 (RIPK3), a central executioner of necroptosis. The physiological relevance of this pathway is highlighted in ischemic stroke, where we found that circulating Tα1 levels were significantly reduced in patients and mice, strongly correlating with disease severity. Genetic deletion of the Tα1-encoding gene Ptma exacerbated stroke injury, whereas therapeutic administration of Tα1 conferred robust neuroprotection and improved functional recovery. Our findings identify a novel thymus-brain signaling pathway, revealing a new neuroprotective function for an immune peptide and an unexpected role for a canonical neuronal receptor. This work establishes Tα1 as a promising dual-action therapeutic candidate, capable of both direct neuronal protection and systemic immunomodulation.