REVIEW article
Front. Mol. Biosci.
Sec. Cellular Biochemistry
The Strategic Breakdown: CHAC Enzymes as Regulators of Glutathione Homeostasis and Disease Implications
Provisionally accepted
- 1University of Münster, Münster, Germany
- 2Charite - Universitatsmedizin Berlin, Berlin, Germany
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This review explores the critical function of the evolutionarily conserved ChaC-like enzyme family as central regulators of intracellular glutathione (GSH) homeostasis, focusing on the mammalian isoforms CHAC1 and CHAC2. We detail how these γ-glutamylcyclotransferases degrade GSH, thereby modulating cellular redox balance and integrating diverse stress signaling pathways. CHAC1 emerges as a key stress-responsive effector, transcriptionally upregulated via the ATF4-CHOP axis during endoplasmic reticulum stress and amino acid deprivation. Its role is especially crucial in the induction of ferroptosis, an iron-dependent cell death pathway, positioning it as a context-dependent modulator of cancer progression, neurotoxicity and neurodegeneration. Furthermore, we examine the opposing roles of CHAC1 and CHAC2 in stem cell fate decisions via NOTCH1 signaling and development. The complex duality of CHAC1 in oncology, acting as both a tumor suppressor by promoting ferroptosis and a potential oncogene in TP53-mutant backgrounds, alongside its functions in neuroprotection and immunity, underscores its therapeutic potential.
Keywords: CHAC1, ChaC2, Glutathione, ferroptosis, Cancer, Botch, Endoplamic reticulum stress
Received: 14 Oct 2025; Accepted: 30 Nov 2025.
Copyright: © 2025 Schröder, Jalilvand, Kahl, Kaiser and Liebau. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Eva Liebau
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