“…Improving our understanding of protein signalling pathways triggered upon target-specific electrophilic modification by native electrophilic signalling molecules may pave a new pathway to targeting moonlighting functions of protein targets. [19,101,102] For example, in Cravatt's pioneering work of mapping LDE responders, he identified that sterile alpha motif and leucine zipper containing kinase (ZAK), one of the topranking hits of HNE, possesses a unique cysteine residue (C22) specific for 'sensing' HNE signals under oxidative stress, but is otherwise functionally silent in the basal state. [87,98,99] Additionally, Aye and co-workers have developed innovative proteomic platforms, such as Targetable Reactive Electrophiles and oXidants (T-REX) [99] and Genome-wide profiling of Reactive-Electrophile and -oXidant sensors (G-REX), [98][99][100] to profile and characterise protein responders that evolve a unique sensor cysteine primed for reactions with native LDE molecules, despite the presence of millimolars of GSH.…”