Numerous clinical studies have demonstrated the influence of vegan diets on cardiovascular health.1 We are particularly interested in the functional impacts of naturally occurring dietary electrophiles found in such diets, which have been linked to chemopreventive actions2 and, more recently, to reduced risks of thrombosis and stroke3 through covalent modification of the protein cysteinome.4 Despite these associations, the consequences of these post-dietary covalent modifications on protein function, cell signalling, and cardiovascular physiology remain largely unexplored.
In our recent investigation, we analysed platelet phenotypes resulting from the irreversible binding of 40+ dietary electrophiles to platelet proteins. This revealed distinct antiplatelet selectivity profiles for naturally occurring isothiocyanates and polyphenols, which notably attenuated platelet responses to ADP stimulation while leaving thrombin-mediated activation unaffected. By integrating a click chemistry–based target enrichment strategy with multiplexed Tandem Mass Tag (TMT) proteomic mapping, we identified protein disulfide isomerase isoform A6 (PDIA6), protein tyrosine kinase 2 beta (Pyk2), and ubiquitin ligases as key targets underlying these unique antithrombotic effects. Importantly, using models of electrolytic injury–induced thrombosis and tail bleeding, we demonstrated that selective inhibition of PDIA6 or Pyk2 is effective in thrombolytic therapy in vivo without increasing bleeding risk. These findings also open a new trajectory for the rational design of safe blood thinners inspired by natural products found in heart-healthy diets.