Abstract WP350: Integrative Proteomic Profiling Reveals Sex-Specific Pathways in Socially Isolated Stroke Patients

Introduction: Ischemic stroke initiates a cascade of molecular events including increased neuroinflammation, immune dysregulation, and vascular injury, yet the biological mechanisms of post-stroke recovery remain poorly understood. In both experimental and clinical studies, social isolation (SI) impairs stroke recovery through distinct immunometabolism and neuroendocrine pathways, and these may differ by sex. Proteomic integration with psychosocial and biological variables has the potential to reveal mechanisms driving stroke disparities and inform targeted interventions. Hypothesis: We hypothesize that stroke triggers sex- and isolation-specific alterations in immune, vascular, and metabolic pathways that drive divergent post-stroke outcomes. Methods: We analyzed plasma proteomic profiling via Single-Run LC-MS/MS in ischemic stroke patients (N=154, 63±14 y, 59 females, 95 males) 24 hours after last known well. Samples were collected from imaging-confirmed strokes. Isolation was measured via the Lubben Social Network Scale and loneliness with the UCLA Loneliness Scale during hospitalization. Results: In males, proteins associated with higher UCLA loneliness scores were significantly enriched for pathways related to coagulation, complement activation, and vascular inflammation. The top-ranking KEGG terms included “Complement and coagulation cascades,” “Platelet activation,” and “Neuroactive ligand receptor interaction.” The enrichment of complement and coagulation pathways reflects systemic thrombo-inflammatory activation, which has been mechanistically linked to blood-brain barrier disruption, microglial priming, and neurovascular injury. In females, loneliness-associated proteins also converged on immune and vascular regulatory pathways, although with distinct signatures compared to males. The top enriched KEGG pathways included “Complement and coagulation cascades,” “Lipid and atherosclerosis,” and “Cytokine-cytokine receptor intera ction.” The prominence of complement proteins such as C3, C4A, and C4B reinforces the role of classical complement activation in shaping neuroimmune responses that influence mood and social behavior. Conclusion: These findings establish that sex and SI fundamentally reprogram post-stroke proteomic landscapes. Defining these context-specific responses offers a path toward precision therapies that address sex differences and mitigate the long-term burden of stroke and social isolation across populations.