Recent advances in computational and experimental screening strategies have facilitated the identification of potential antithrombotic agents targeting protease-activated receptor 1 (PAR1). In this critique, we evaluate the study by (Huang et al., Cardiovasc drugs Ther, 2025), which employed molecular docking, platelet aggregation assays, and in vivo thrombosis models to identify PAR1 antagonists from Polygonum amplexicaule. While the integrative approach is commendable, we highlight critical limitations, including the heavy reliance on in silico docking to infer receptor-specific pharmacological activity without confirmatory functional assays. Given the conformational flexibility of PAR1 and the complex signaling networks regulating platelet activation, docking scores alone are insufficient to establish functional antagonism or selectivity. Furthermore, the translational limitations of commonly used murine thrombosis and bleeding models, alongside interspecies differences in PAR signaling, restrict clinical extrapolation. Finally, inadequate characterization of pharmacokinetics, dose-response relationships, and chronic toxicity raises concerns regarding therapeutic feasibility. Collectively, these limitations underscore the need for more rigorous mechanistic validation, advanced translational models, and comprehensive pharmacological profiling to strengthen the development pipeline for PAR1-targeted antithrombotic agents.
