A druggable redox switch on SHP1 controls macrophage inflammation

Abstract Immunological proteins are major disease targets, yet most remain undrugged. Post-translational redox modification of cysteine residues has emerged as an important mode of immune cell regulation, particularly in macrophage cytokine responses. Here, we develop a strategy for systematic discovery and small-molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 in vivo redox-regulated cysteines across diverse immune-relevant protein domains. We demonstrate how these sites enable cysteine-directed pharmacology through discovery of a novel cysteine activation site on the immune regulator SHP1. Targeting Cys102, we develop a highly selective covalent agonist, SCA, which binds the N-SH2 domain to relieve autoinhibition and activate SHP1. In mouse and human macrophages, SCA selectively engages SHP1 Cys102, antagonizing IRAK signaling and LPS-induced pro-inflammatory cytokine production. Together, this work identifies a druggable cysteine redox switch controlling macrophage cytokine responses and provides a compendium of redox-regulated sites for therapeutic development. Competing Interest Statement E.T.C. is co-founder of Matchpoint Therapeutics and Aevum Therapeutics. J.C. is a co-founder of Matchpoint Therapeutics, scientific co-founder of M3 Bioinformatics & Technology Inc., and consultant and equity holder for Soltego and Allorion. N.S.G. is a founder, science advisory board member (SAB) and equity holder in Syros, C4, Allorion, Lighthorse, Inception, Matchpoint, Shenandoah (board member), Larkspur (board member) and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, Springworks, Interline and Sanofi. M.Y.N., M.N.N., G.D., E.T.C., J.C., T.Z. and N.S.G. are inventors on a patent WO/2025/109475 for the SHP1 compounds described in this work. All other authors declare no competing interests. Footnotes This version of the manuscript has been revised to Update author affiliation