Regulation of histones in thromboinflammation.

Extracellular histones, once regarded solely as nuclear structural proteins, are now recognized as potent mediators of thrombo-inflammation which is the pathological interface of coagulation and immunity. Released during necrosis, apoptosis, and neutrophil extracellular trap (NET) formation, histones act as damage-associated molecular patterns (DAMPs), engaging receptors such as Toll-like receptors (TLR2, TLR4, TLR9) to trigger endothelial dysfunction, platelet activation, and cytokine release. Post-translational modifications (PTMs), including citrullination, acetylation, and methylation, further modulate histone immunogenicity, cytotoxicity, and procoagulant potential. These mechanisms amplify thrombin generation, impair anticoagulant pathways, and promote vascular permeability, positioning histones as central drivers of immunothrombosis in sepsis, stroke, ARDS, COVID-19, and autoimmune disorders. Circulating histones and nucleosomes are emerging as biomarkers for disease severity and prognosis. Therapeutic strategies targeting histones, such as neutralizing antibodies, heparin derivatives, PAD inhibitors, and activated protein C, show promise in mitigating histone-driven pathology. This review highlights mechanistic insights into histone biology and explores translational opportunities for targeted interventions at the intersection of inflammation and thrombosis.