Long, Marcus J. C.Aye, Yimon2022-07-182022-07-182022-07-182022-09-0110.1016/j.bmcl.2022.128766https://infoscience.epfl.ch/handle/20.500.14299/189341WOS:000816032200014Here we draw insights from the latest serendipitous findings made on the opposing roles of a proposed drug-target protein Keap1. We weigh up how natural reactive electrophiles and electrophilic small-molecule drugs in clinical use directly impinge on seemingly conflicting, yet both Keap1-electrophile-modification-dependent, cell -survival-vs. cell-death-promoting behaviors. In the process, we convey how understanding reactive chemical-signal regulation at the single-protein-specific level is an enabling necessity in deconstructing otherwise intricate reactive-small-molecule-responsive cellular pathways. We hope this opinion piece further spurs the broader interests of basic and pharmaceutical research communities toward better understanding of molecular mechanisms underpinning reactive small-molecule-regulated signaling subsystems.Chemistry, MedicinalChemistry, OrganicPharmacology & PharmacyChemistrykeap1nrf2antioxidant responseelectrophile signalingtecfiderainnate immune responsetext::journal::journal article::research article