Given that neuroinflammation contributes to the BBB disruption and tPA’s neurovascular complications, we logically hypothesize that HMGB1 may potentiate the risk of tPA-associated complications, while blocking HMGB1-induced inflammation could protect BBB integrity, subsequently reducing tPA-induced hemorrhage during thrombolytic therapy for ischemic stroke. The gene discussed is HMGB1; the disease is ischemic stroke.