ArticleRedox biology2026
The electrophilic metabolite of kynurenine, kynurenine-CKA, requires C151 in Keap1 to derepress Nrf2.
Article in Redox biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Compensation for impaired sensing of selenoprotein deficiency by alternative cysteine residues in KEAP1.Redox biology · 2026Article
- Keap1-Kelch-targeting protein-protein interaction inhibitors, but not reversibly-binding electrophiles, increase the thermostability of Keap1 in the cellular environment.RSC chemical biology · 2026Article
- Cell Signaling by Tryptophan Catabolism.Biochemistry · 2026Review
- The role of tryptophan-AhR signaling in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD): implications for therapeutic strategies.Frontiers in immunology · 2026Review
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Abstract
The Kelch-like ECH-associated protein 1/Nuclear factor-erythroid 2 p45-related factor 2 (Keap1/Nrf2) system responds to a wide array of structurally diverse small molecules, of both exogenous and endogenous origin, by inducing a robust cytoprotective program that allows adaptation during oxidative, metabolic and inflammatory stress. Here, we report that exposure to the tryptophan metabolite kynurenine and its electrophilic derivative kynurenine-carboxyketoalkene (Kyn-CKA) leads to an increase in the abundance of transcription factor Nrf2 and induction of Nrf2-target genes, including NAD(P)H:quinone oxidoreductase 1 (NQO1), in murine and human cells. Additionally, both kynurenine and Kyn-CKA activate the aryl hydrocarbon receptor (AhR). Using cellular thermal shift assays, we found that Kyn-CKA increases the thermal stability of Keap1-mCherry fusion protein, but not free mCherry, indicating target engagement of Keap1, the principal repressor of Nrf2. Critically, the ability of Kyn-CKA to increase the abundance of Nrf2 and expression of NQO1 in mouse embryonic fibroblasts (MEFs) expressing wild-type Keap1 was greatly diminished in C151S-Keap1 mutant MEFs. Furthermore, Kyn-CKA reacts with Keap1 C151 much faster in vitro than with the small molecule thiol N-acetyl cysteine, suggesting that Kyn-CKA is targeted to C151 by the surrounding active site. Experiments in wild-type, AhR-knockout, and Nrf2-knockout primary murine bone marrow-derived macrophages showed that Nrf2 is required for the acute anti-inflammatory activity of Kyn-CKA, whereas AhR is dispensable. Together, these findings demonstrate that Kyn-CKA requires C151 in Keap1 to derepress Nrf2 and reveal that Nrf2, but not AhR, is a main contributor to the anti-inflammatory activity of Kyn-CKA in macrophages.
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