Given the rapid release of HMGB1 from damaged neurons after stroke and its accumulation in serum as early as 1 h after MCAO20, we propose two potential sources of HMGB1 following cerebral ischemia: (1) locally synthesized HMGB1 within the liver, acting in an autocrine or paracrine manner, and (2) transported HMGB1 originating from damaged brain tissue, reaching the liver via the bloodstream and exerting its effect in an endocrine manner. Here, HMGB1 is linked to stroke disorder.