The strategic breakdown: CHAC enzymes as regulators of glutathione homeostasis and disease implications

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 <i>via</i> 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 <i>via</i> 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 <i>TP53</i>-mutant backgrounds, alongside its functions in neuroprotection and immunity, underscores its therapeutic potential.