Thrombosis is the leading cause of death and disability in Australia and globally. However, all approved antithrombotic drugs (including anticoagulants and antiplatelet agents) have the potential risk of causing uncontrollable bleeding during accidental overdose. Bleeding risk is the paramount consideration when evaluating the performance of antithrombotic leads in modern (pre)clinical trials; we thereby focus on studying the natural antiplatelet agents found in healthy diets with a view to identify safer protein targets for future antithrombotic discovery campaign.^1,2 Here we demonstrated that sulforaphane (SFN) - a predominant electrophilic lipid isolated from cruciferous vegetables - exhibits a novel mode of covalent inhibition against human platelet aggregation under thrombotic conditions, with minimal bleeding risk and improves recanalisation outcomes demonstrated in in-vivo study. An activity‐based probe of SFN was developed to map the bona fide target responsible for the antiplatelet phenotype - protein disulfide isomerase A6 (PDIA6), which SFN selectively modified the non-catalytic cysteines leading to partially inhibition of its enzymatic function. Interactome mapping analysis revealed the important role of PDIA6 in regulating platelet activation under shear-induced thrombotic conditions.⁴ Taken together, our approach successfully identified PDIA6 as the potential safer antiplatelet target, and the selective inhibition by SFN could exhibit a greater bias towards thrombosis, hence reducing the risk associated with conventional antiplatelet therapies.