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A druggable redox switch on SHP1 controls macrophage inflammation
Mei Ying Ng1,2, Meredith N Nix3,4, Guangyan Du3
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nature Chemical Biology
|March 13, 2026
Summary
Researchers identified druggable cysteine sites on immunological proteins, enabling new drug development. They discovered a specific cysteine switch in SHP1 that controls macrophage cytokine production, offering a novel therapeutic target.
Area of Science:
- Biochemistry
- Immunology
- Proteomics
Background:
- Immunological proteins are key disease targets, but many are undrugged.
- Cysteine redox modifications regulate immune cell function, especially macrophage cytokine responses.
Purpose of the Study:
- To develop a strategy for discovering and functionalizing redox-regulated cysteines on immunological proteins.
- To identify novel cysteine sites for therapeutic intervention in immune regulation.
Main Methods:
- Deep redox proteomics to identify in vivo redox-regulated cysteines.
- Discovery and characterization of a cysteine activation site on SHP1.
- Development of a selective covalent agonist (SCA) targeting SHP1 C102.
Main Results:
- Annotated 788 in vivo redox-regulated cysteines across immune-relevant proteins.
- Identified and targeted SHP1 C102 with SCA, a selective covalent agonist.
- Demonstrated SCA's ability to antagonize inflammatory signaling and cytokine production in macrophages.
Conclusions:
- Identified a druggable cysteine redox switch controlling macrophage cytokine responses.
- Provided a compendium of redox-regulated sites for future therapeutic development.
- Established cysteine-directed pharmacology as a viable strategy for immune targets.
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