Abstract
<jats:p>Murine serine protease inhibitor clade A member 3N (SERPINA3N) and its human homolog SERPINA3 are injury-associated molecules induced in virtually all neurological conditions including ischemic stroke. Clinically, SERPINA3 is elevated in stroke patients, correlating with severe brain pathology and worse neurological outcomes. Yet, the exact cellular sources and therapeutic value of SERPINA3N/SERPINA3 in the ischemic brain remain elusive. Here, we report that oligodendrocytes are the major sources of SERPINA3/SERPINA3N and that SERPINA3N exerts neurotoxic effects in experimental cerebral ischemia. Given SERPINA3N's secretory nature, we used knock-in Serpina3n tdTom reporter mice to define its temporospatial evolution. The tdTom signal was barely detectable by day1 but gradually increased from day 3 through day 7 following cerebral ischemia. The majority of tdTom+ cells were identified as oligodendrocytes and astrocytes with fewer found in neurons or microglia. This cellular identity was corroborated by meta-analysis of single-cell transcriptomics datasets and human ischemic stroke brain data. Antagonizing SERPINA3N attenuated blood-brain barrier disruption, neuroinflammation, and neuronal damage and improved neurological function in a mouse model of cerebral ischemia. These findings resolve a longstanding debate regarding the cellular origins of SERPINA3N, identifying oligodendrocytes as its major source. Our studies highlight SERPINA3N antagonism as a possible therapeutic intervention for ischemic stroke, providing new insights for precision therapies that target oligodendroglia- or astroglia-specific SERPINA3N.</jats:p>