Riluzole preserves brain endothelial integrity in ischemic stroke via SLC7A11-dependent GPX4 and HIF-1α/VEGFA signaling.

Riluzole, an FDA-approved neuroprotective agent, was investigated for its therapeutic potential in ischemic stroke. Transcriptomic profiling of human brain microvascular endothelial cells (hBMECs) subjected to oxygen-glucose deprivation/reperfusion (OGD/R) identified a pivotal role for the cystine/glutamate antiporter SLC7A11. We found that riluzole activates SLC7A11, thereby triggering a dual protective mechanism: it strengthens cellular antioxidant capacity by upregulating GPX4 while simultaneously enhancing proangiogenic signaling through the HIF-1α/VEGFA pathway. Consequently, riluzole attenuated OGD/R-induced endothelial injury and, in a mouse stroke model, reduced blood-brain barrier disruption and improved neurological outcomes. Our study reveals a previously unrecognized cerebrovascular protective mechanism of riluzole, establishing SLC7A11 as its key mediator. This SLC7A11-dependent dual-pathway action represents a substantive advance in understanding riluzole's therapeutic biology beyond its established roles in the central nervous system.