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Abstract Background

Thrombosis is the key driver for ischemic events, including stroke, which is the leading cause of global mortality. However, current antithrombotic therapies carry substantial bleeding risks. Targeting protease-activated receptor-1 (PAR-1), a thrombin-activated receptor central to thrombus growth, represents a promising antithrombotic strategy for safer intervention.

Material and Methods

we mined the venom gland transcriptome of Conus spp., applied in silico Furin cleavage prediction, and synthesized and screened the anti-PAR-1 activity of a series of conotoxin-derived peptides.

Results

Cb-26 exhibited the strongest but reversible activity in inhibiting PAR-1-mediated platelet activation and aggregation in vitro. Crucially, Cb-26 inhibited platelet adhesion, neutrophil extracellular traps formation, and thrombus growth under shear conditions in whole blood from healthy donors. In murine models, Cb-26 significantly delayed carotid occlusion and reduced cerebral infarct size in photochemical-induced ischemic stroke, without affecting blood coagulation and bleeding time.

Conclusion

These results suggest that Cb-26 is a selective and reversible PAR-1 antagonist and represents a promising antithrombotic candidate without apparent bleeding side effects.

Keywords platelet - protease-activated receptor - thrombosis - stroke - conotoxin Contributors' Statement

A.W., G.X., and Z.C.: contributed to investigation and writing—review and editing. T.W. contributed to conceptualization, investigation, data curation, formal analysis, and writing—original draft. H.C. and S.F. contributed to investigation and data curation. X.C. contributed to investigation. M.L. contributed to data curation and writing—review and editing. C.S. contributed to writing—review and editing. R.L. contributed to supervision and writing—review and editing.

‡ These authors contributed equally to this work.

Publication History

Received: 26 July 2025

Accepted after revision: 16 February 2026

Accepted Manuscript online:
19 February 2026

Article published online:
03 March 2026

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