Bat-derived oligopeptide LE6 inhibits the contact–kinin pathway and harbors anti-thromboinflammation and stroke potential.

Thrombosis and inflammation predominantly contribute to the onset and progression of is-chemic stroke. The contact-kinin pathway initiated by plasma kallikrein (PK) and activated factor XII (FXIIa), functions bidirectionally with the coagulation and inflammation cascade response, thus emerging a direction for the development of therapeutic drugs for ischemic stroke. In this study, we identified a bat (Myotis myotis Borkhausen)-derived oligopeptide LE6 (Leu-Ser-Glu-Glu-Pro-Glu, 702 Da), demonstrating potential in stroke therapy by tar-geting the inhibition of the contact kinin pathway. Notably, LE6 demonstrating potential in stroke therapy by exerting an inhibitory effect on PK and FXIIa, with inhibition constants of 43.97 μM and 6.37 μM, respectively. In vitro, analyses revealed that LE6 prolonged plasma recalcification time and activated partial thromboplastin time. And in murine models, LE6 inhibited carrageenan‑induced mouse tail thrombosis, FeCl3-induced carotid artery throm-bosis, and photochemically induced intracerebral thrombosis. Furthermore, LE6 significant-ly decreased inflammation and stroke injury in transient middle cerebral artery occlusion models. Importantly, the low toxicity, hemolytic, and low bleeding potential of LE6 and to-gether with its synthetic simplicity, underscore its potential clinical availability. In conclu-sion, LE6, as an inhibitor of FXIIa and PK, is beneficial in stroke therapy by reducing in-flammation and inhibiting thrombus formation.