FPR1 is a G protein-coupled receptor that functions as a critical sensor of damage-associated molecular patterns and microbial-derived signals in innate immunity. 1 The receptor binds endogenous ligands including N-formylated peptides, particularly those derived from mitochondria during cellular stress. 2 Mechanistically, FPR1 activation triggers multiple inflammatory signaling cascades. In microglia and macrophages, FPR1 stimulation promotes mitochondrial dysfunction and pro-inflammatory responses that amplify brain injury. 32 The receptor also participates in bidirectional cell-cell communication; tumor-derived ANXA1 engaging FPR1 on microglia and glioma cells suppresses anti-tumor immunity and promotes immune evasion. 4 Disease relevance spans multiple CNS and cardiovascular conditions. In multiple sclerosis, elevated FPR1 expression in microglia and infiltrating macrophages correlates with disease progression and axonal degeneration. 3 Following intracerebral hemorrhage, circulating mitochondrial N-formyl peptides activate FPR1, exacerbating brain edema and neurological deficits. 2 In glioblastoma, ANXA1-FPR1 signaling limits tumor-specific immunity, and elevated FPR1 associates with poor outcomes. 4 FPR1 also contributes to hypertension through eNOS uncoupling mechanisms. 5 Clinically, FPR1 antagonists (T0080/T-0080) that penetrate the blood-brain barrier show therapeutic promise in reducing inflammation and neurodegeneration across multiple brain diseases.