Advancements in research on the thrombo-inflammation mechanisms mediated by factor XII in ischemic stroke.

Ischemic stroke (IS) is a major cause of mortality and disability, with thrombo-inflammation constituting a core pathophysiological mechanism. This process is closely linked to coagulation cascade activation, endothelial injury, immune cell infiltration, and neuronal damage. Coagulation factor XII (FXII), a key mediator of the contact activation pathway, has emerged as a promising therapeutic target due to its dual role in pathological thrombosis and immune regulation, without compromising physiological hemostasis. However, the clinical translation of FXII-targeted therapies is hindered by paradoxical observations. Recent studies highlight that FXII's functional complexity stems from its structural and spatial heterogeneity: full-length FXII derived from the liver and short FXII mRNA isoforms expressed in neurons mediate distinct biological effects. While FXII contributes to neuroinflammation and vascular injury via endothelial-platelet-neutrophil interactions, neuron-derived FXII exhibits neuroprotective effects through HGF-mediated signaling pathways. Additionally, circulating FXIIa promotes vascular remodeling by enhancing endothelial growth factor (VEGF) release. This review summarizes the multifaceted regulatory mechanisms of FXII in IS, focusing on its structure, distribution, preclinical-clinical paradox, and current therapeutic strategies. Special emphasis is placed on its domain-specific functions and the neuroprotective effects of FXII.