Precision Covalent Drug Discovery Inspired by Endogenous Electrophilic Signalling in Immune Cells

Immune cells possess an intrinsic covalent signalling system in which endogenous electrophilic species function as molecular regulators of cellular state that integrate metabolic activity, oxidative stress, and inflammatory signals. Lipid peroxidation-derived electrophiles, enzymatically generated electrophilic lipid mediators, nitro-fatty acids, and metabolite-derived electrophiles selectively modify reactive amino acid residues within signalling proteins to regulate immune cell differentiation, metabolic adaptation, stress responses, and tissue responses. This perspective highlights that endogenous electrophilic signalling provides a biological blueprint for the development of next-generation precision covalent immunotherapeutics. Beyond exploiting electrophilic chemistry as a reactive pharmacological strategy, emerging insights reveal that immune cells naturally employ regulated covalent modifications to achieve stimulus-dependent control of signalling networks. Advances in chemoproteomics, structural biology, systems immunology, computational chemistry, and targeted delivery technologies are enabling the identification of electrophile-sensitive regulatory targets and the rational design of selective covalent modulators. The discussion includes how the principles derived from endogenous electrophilic signalling can guide therapeutic innovation across major immunotherapeutic areas, including chronic inflammatory diseases, cancer immunology, inflammasome-driven disorders, fibrotic disease, neuroinflammation, and vascular immunometabolic disorders. By translating endogenous covalent regulatory mechanisms into precision drug design strategies, electrophile-guided pharmacology offers an emerging strategy for developing therapies that reprogramme immune cell states, restore immune homeostasis, and achieve stimulus-dependent modulation of disease-associated immune responses.