A druggable redox switch on SHP1 controls macrophage inflammation

Mei Ying Ng; Meredith N Nix; Guangyan Du; Ivan Davidek; Nils Burger; Sanghee Shin; Sean Toenjes; Haruna Takeda; Megan Cheah Xin Yan; Bingsen Zhang; Haopeng Xiao; Shelley M Wei; Hyuk-Soo Seo; Sirano Dhe-Paganon; Thomas E Wales; John R Engen; Evanna L Mills; Jianwei Che; Tinghu Zhang; Nathanael S Gray; Edward T Chouchani

doi:10.1038/s41589-026-02163-8

A druggable redox switch on SHP1 controls macrophage inflammation

Nat Chem Biol. 2026 Mar 12:10.1038/s41589-026-02163-8. doi: 10.1038/s41589-026-02163-8. Online ahead of print.

Authors

Mei Ying Ng^#^{1

2}, Meredith N Nix^#^{3

4}, Guangyan Du³, Ivan Davidek³, Nils Burger^{1

2}, Sanghee Shin^{1

2}, Sean Toenjes³, Haruna Takeda^{1

2}, Megan Cheah Xin Yan^{1

2}, Bingsen Zhang^{1

2}, Haopeng Xiao^{1

2}, Shelley M Wei^{1

2}, Hyuk-Soo Seo¹, Sirano Dhe-Paganon¹, Thomas E Wales⁵, John R Engen⁵, Evanna L Mills^{6

7}, Jianwei Che⁸, Tinghu Zhang⁹, Nathanael S Gray¹⁰, Edward T Chouchani^{11

12

13}

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
³ Department of Chemical and Systems Biology, CHEM-H and SCI, Stanford Medical School, Stanford University, Stanford, CA, USA.
⁴ Department of Chemistry, Stanford University, Stanford, CA, USA.
⁵ Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
⁶ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Department of Immunology, Harvard Medical School, Boston, MA, USA.
⁸ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. jianwei_che@dfci.harvard.edu.
⁹ Department of Chemical and Systems Biology, CHEM-H and SCI, Stanford Medical School, Stanford University, Stanford, CA, USA. ztinghu8@stanford.edu.
¹⁰ Department of Chemical and Systems Biology, CHEM-H and SCI, Stanford Medical School, Stanford University, Stanford, CA, USA. nsgray01@stanford.edu.
¹¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. edwardt_chouchani@dfci.harvard.edu.
¹² Department of Cell Biology, Harvard Medical School, Boston, MA, USA. edwardt_chouchani@dfci.harvard.edu.
¹³ Howard Hughes Medical Institute, Chevy Chase, MD, USA. edwardt_chouchani@dfci.harvard.edu.

^# Contributed equally.

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 C102, 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 C102, antagonizing interleukin-1 receptor-associated kinase signaling and lipopolysaccharide-induced proinflammatory 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.

Abstract

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