Affinage

CHAC1

Glutathione-specific gamma-glutamylcyclotransferase 1 · UniProt Q9BUX1

Length
222 aa
Mass
24.4 kDa
Annotated
2026-06-09
68 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHAC1 is a cytosolic γ-glutamyl cyclotransferase that specifically degrades intracellular reduced glutathione, and through this enzymatic depletion of GSH it drives oxidative stress, ferroptosis, and apoptosis across diverse cell types (PMID:23070364, PMID:31189567, PMID:40267214). Its substrate specificity is narrow — it acts on glutathione but not other γ-glutamyl peptides — and catalysis depends on a defined active-site surface in which residues such as Y38–L41, D68, R72, E115, and Y143 contact glutathione; catalytically dead mutants fail to deplete GSH or produce downstream phenotypes (PMID:23070364, PMID:36456186). CHAC1 functions principally as a downstream effector of the integrated stress response: it is a proapoptotic component of the ATF4–ATF3–CHOP arm of the UPR, with ATF4 (and ATF3) directly transactivating the CHAC1 promoter through ATF/CRE and CARE elements (PMID:19109178, PMID:25931127, PMID:39836526), and it operates downstream of both PERK and GCN2 branches depending on the stress, mediating cystine-starvation necroptosis and ferroptosis (PMID:29383104). In vivo genetic studies establish that CHAC1's GSH-degrading activity is required for pathology: Chac1 haploinsufficiency or catalytic inactivation preserves glutathione, suppresses lipid peroxidation, and confers resistance to ferroptosis-driven kidney disease (PMID:39836526, PMID:40267214), although GSH preservation alone is insufficient to prevent cachexia-induced muscle wasting (PMID:37014882). Beyond GSH degradation, CHAC1 binds Notch3 and inhibits its activation (PMID:27986595), bridges UBA2 and PKM2 to enhance PKM2 SUMOylation and nuclear translocation driving the Warburg effect (PMID:39368995), and is required for glutathione-redox-dependent calcium transients during zebrafish development (PMID:31189567).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2009 High

    Established CHAC1 as a proapoptotic effector positioned specifically within the ATF4-ATF3-CHOP arm of the UPR, distinguishing it from the parallel XBP1/ATF6 branches.

    Evidence siRNA knockdown of UPR transcription factors plus CHAC1 gain/loss-of-function with apoptosis readouts (TUNEL, PARP cleavage, AIF translocation)

    PMID:19109178

    Open questions at the time
    • Molecular activity of CHAC1 not yet defined at this stage
    • Direct promoter binding not yet demonstrated
  2. 2012 High

    Defined the molecular function of CHAC1 as a γ-glutamyl cyclotransferase that specifically degrades glutathione, and showed this enzymatic activity is required for its proapoptotic effect.

    Evidence In vitro enzymatic assays and yeast overexpression with catalytic E>Q mutants, glutathione depletion measurements

    PMID:23070364

    Open questions at the time
    • Active-site architecture not resolved
    • Mammalian in vivo relevance not yet established
  3. 2015 High

    Identified the cis-regulatory basis of CHAC1 induction, mapping direct ATF4/ATF3 binding to ATF/CRE and ACM promoter elements and confirming enzymatic GSH depletion in human cells.

    Evidence Promoter deletion luciferase reporters, EMSA, ChIP, and WT-vs-catalytic-mutant GSH measurement in HEK293

    PMID:25931127

    Open questions at the time
    • Cell-type-specific cofactors not addressed
    • Quantitative contribution of each element in vivo unknown
  4. 2016 Medium

    Revealed both negative transcriptional control and a non-enzymatic moonlighting function, with TRIB3 repressing CHAC1 and CHAC1 binding Notch3 to inhibit its signaling.

    Evidence Trib3-KO MEFs with promoter analysis and rescue; transcriptome profiling, Co-IP, and apoptosis/ROS/calcium/mitochondrial assays in glioblastoma cells

    PMID:27526673 PMID:27986595

    Open questions at the time
    • CHAC1-Notch3 interaction from single Co-IP without reciprocal/structural validation
    • Whether Notch3 inhibition is enzyme-dependent unresolved
  5. 2017 Medium

    Extended CHAC1's effector role to a second stress branch, showing it executes GCN2-eIF2α-ATF4-driven necroptosis and ferroptosis under cystine starvation, independent of PERK.

    Evidence CHAC1 siRNA with GSH measurement and pharmacological cell-death dissection (Nec-1, ferrostatin-1, deferoxamine) in TNBC cells

    PMID:29383104

    Open questions at the time
    • Single lab
    • Branch selectivity between PERK and GCN2 not mechanistically explained
  6. 2018 Medium

    Demonstrated that CHAC1 enzymatic GSH degradation has genotoxic consequences, linking H. pylori-induced CHAC1 to ROS accumulation and TP53 mutation.

    Evidence WT-vs-catalytic-mutant overexpression, siRNA, TP53 sequencing, GSH/ROS measurement in AGS gastric cells

    PMID:29632819

    Open questions at the time
    • Direct link between specific ROS species and mutation spectrum not established
    • Single lab
  7. 2019 High

    Established a developmental and physiological role beyond cell death, showing GSH-redox-dependent CHAC1 activity is required for calcium transient generation in vivo.

    Evidence Zebrafish morpholino knockdown with WT vs catalytically-inactive rescue, GCaMP6s calcium imaging, Grx1-roGFP2 redox sensing

    PMID:31189567

    Open questions at the time
    • Molecular link between redox potential and calcium machinery not defined
    • Mammalian conservation of this role untested
  8. 2020 Medium

    Refined transcriptional logic by showing ATF4 acts through synergistic ATF/CRE and CARE elements while CHOP exerts an indirect inhibitory effect, complicating the simple ATF4-CHOP-CHAC1 chain.

    Evidence Promoter-luciferase, deletion/mutation analysis, IM-EMSA for ATF4 and CHOP in human and mouse cells

    PMID:33102815

    Open questions at the time
    • Mechanism of indirect CHOP repression unresolved (no direct binding detected)
    • Single lab
  9. 2022 Medium

    Provided structural insight into substrate recognition and uncovered additional transcriptional repression via DJ-1-ATF3 interaction.

    Evidence Molecular docking/MD/MMGBSA with yeast point-mutant validation of active-site residues; BiFC of DJ-1-ATF3 with promoter-binding and GSH assays

    PMID:35988816 PMID:36456186

    Open questions at the time
    • No experimental crystal/cryo-EM structure
    • In vitro enzymatic reconstitution of active-site mutants not directly reported
  10. 2023 Medium

    Separated CHAC1's enzymatic and disease functions and added a direct protein partner, showing catalytic inactivation preserves muscle GSH yet fails to prevent cachexia, while MIA3 binds and stabilizes CHAC1.

    Evidence CRISPR knock-in of enzyme-inactivating mutation in mice with GSH/phenotype readouts; Co-IP, confocal, MIA3 KO with GSH/proliferation assays

    PMID:37014882 PMID:37948019

    Open questions at the time
    • GSH-independent contribution to cachexia not identified
    • MIA3-CHAC1 functional mechanism from single lab
  11. 2024 Medium

    Uncovered a metabolic moonlighting function and additional post-transcriptional control, with CHAC1 bridging UBA2-PKM2 SUMOylation and m6A/YTHDF2 destabilizing CHAC1 mRNA.

    Evidence MS proteomics, Co-IP, SUMOylation and fractionation assays, ChIP for E2F1; MeRIP/RIP, mRNA half-life, ferroptosis assays

    PMID:39368995 PMID:39667319

    Open questions at the time
    • Whether scaffold function requires enzymatic activity unknown
    • Single lab for each mechanism
  12. 2025 High

    Consolidated CHAC1 as a causal in vivo mediator of ferroptotic disease and mapped an extensive regulatory network (ATF4 direct binding, BACH1, EGR1, H3K9ac/P300, NUPR1, miR-383-3p, XRN2/GDIL lncRNA).

    Evidence ChIP-seq/qPCR and Chac1 KO/haploinsufficient mice across kidney, cardiac, and other ferroptosis models; multiple promoter, Co-IP, luciferase, and RNA-stability assays

    PMID:39129295 PMID:39836526 PMID:39893168 PMID:40267214 PMID:40947783 PMID:41093083 PMID:41750596 PMID:42019644

    Open questions at the time
    • Many individual regulators validated in single labs/contexts
    • Integration and hierarchy among regulators not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how CHAC1's enzymatic GSH-degrading activity is mechanistically separated from its non-enzymatic moonlighting roles (Notch3 inhibition, PKM2 SUMOylation scaffolding) and whether these share or diverge in their structural determinants.
  • No experimental high-resolution structure of human CHAC1
  • Enzyme-independence of scaffold/binding functions not tested with catalytic mutants
  • Physiological relevance of moonlighting roles relative to GSH degradation unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0060090 molecular adaptor activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1430728 Metabolism 2
Partners
ATF3ATF4MIA3NOTCH3PKM2UBA2

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 ChaC1 and its homologues function as γ-glutamyl cyclotransferases that specifically degrade glutathione (but not other γ-glutamyl peptides) both in vivo and in vitro; catalytically dead E>Q mutants failed to deplete glutathione or enhance apoptosis in yeast, establishing enzymatic activity as required for these effects. In vitro enzymatic assays, yeast overexpression with catalytic mutants, glutathione depletion measurements EMBO reports High 23070364
2009 CHAC1 is a downstream component of the ATF4-ATF3-CHOP arm of the unfolded protein response (UPR); it is not activated by the parallel XBP1 or ATF6 branches. CHAC1 overexpression enhanced apoptosis and its knockdown suppressed apoptosis (TUNEL, PARP cleavage, AIF nuclear translocation), placing it as a proapoptotic effector downstream of ATF4. siRNA knockdown of ATF4/ATF3/CHOP/XBP1/ATF6, CHAC1 overexpression plasmids, TUNEL assay, PARP cleavage, AIF nuclear translocation, expression microarray Journal of immunology High 19109178
2015 Human CHAC1 promoter is transactivated by ATF4 and ATF3 through two cis-elements: a -267 ATF/CRE site and a novel -248 ATF/CRE modifier (ACM) element. Direct binding of ATF4 and ATF3 (and C/EBPβ) at these elements was confirmed by EMSA and ChIP. CHAC1 overexpression robustly depleted glutathione in HEK293 cells; a catalytic mutant failed to do so. Luciferase reporter with promoter deletion/mutation analysis, immunoblot-EMSA, ChIP, glutathione measurement in cells overexpressing WT vs. catalytic mutant CHAC1 The Journal of biological chemistry High 25931127
2016 TRIB3 represses CHAC1 expression downstream of ATF4, protecting cells from arsenite-induced glutathione depletion and death. Two regulatory elements in the Chac1 promoter mediate induction by arsenite/ATF4 and suppression by TRIB3. Chac1 silencing in Trib3-deficient cells restored glutathione and rescued arsenite sensitivity, establishing TRIB3 as an upstream negative regulator of CHAC1. Trib3-knockout MEFs, Chac1 siRNA, promoter analysis, glutathione measurements, cell viability assays Biochimica et biophysica acta Medium 27526673
2016 In glioblastoma cells, TMZ-induced CHAC1 expression is controlled transcriptionally by the JNK1/c-JUN pathway. CHAC1 binds to the Notch3 protein and inhibits Notch3 activation, thereby attenuating Notch3-mediated downstream signaling; CHAC1 overexpression induced apoptosis via caspase-3/9 activation, ROS generation, increased intracellular calcium, and loss of mitochondrial membrane potential. Transcriptome microarray, CHAC1 overexpression/knockdown, co-immunoprecipitation (CHAC1–Notch3 binding), caspase activation assays, ROS measurement, mitochondrial membrane potential assay Neuropharmacology Medium 27986595
2017 CHAC1 degrades glutathione in TNBC cells under cystine starvation downstream of the GCN2-eIF2α-ATF4 pathway (not PERK). CHAC1 knockdown rescued GSH levels and prevented cystine-starvation-induced necroptosis and ferroptosis, placing CHAC1 as a functional effector of GCN2-driven cell death. CHAC1 siRNA knockdown, GSH measurement, cell death assays with pathway inhibitors (Nec-1, MLKL inhibitor, deferoxamine, ferrostatin-1), GCN2/PERK pathway analysis Oncotarget Medium 29383104
2018 cagA-positive H. pylori infection triggers CHAC1 overexpression in gastric epithelial cells, leading to glutathione degradation, ROS accumulation, and TP53 somatic mutations. A catalytically inactive CHAC1 mutant did not induce TP53 mutations, confirming that CHAC1's glutathione-degrading enzymatic activity is necessary for ROS-mediated genotoxicity. CHAC1 overexpression (WT vs. catalytic mutant), CHAC1 siRNA, TP53 mutation sequencing, glutathione and ROS measurement in AGS cells FEBS open bio Medium 29632819
2019 Zebrafish Chac1 is a glutathione-degrading enzyme (acting only on reduced GSH) that is required for calcium signaling during embryonic development. chac1 morphants showed attenuated calcium transients (measured by GCaMP6s) and developmental defects in myotome, brain, and heart; these phenotypes were rescued by WT Chac1 but not catalytically inactive Chac1. Intracellular glutathione redox potential (monitored by Grx1-roGFP2) is an upstream activator of calcium signaling. Zebrafish morpholino knockdown, rescue with WT and catalytically inactive Chac1, live calcium imaging (GCaMP6s), glutathione redox sensor (Grx1-roGFP2) The Biochemical journal High 31189567
2020 CHAC1 transcription in humans and mice is induced by ATF4 through synergistic ATF/CRE and CARE (amino acid response element) sequences in the CHAC1 promoter. CHOP (DDIT3) exerts a novel inhibitory effect on CHAC1 transcription via the ATF/CRE motif through an indirect mechanism; direct binding of CHOP to the ATF/CRE was not detected by EMSA. Promoter-luciferase reporter assays, deletion/mutation analysis, IM-EMSA for ATF4 and CHOP binding, ATF4 overexpression in human and mouse cells Biochemistry and biophysics reports Medium 33102815
2022 Active-site residues of human ChaC1 forming direct interactions with glutathione were identified: Y38, G39, S40, L41 (38-YGSL-41), D68, R72, E115, and Y143. Residues exclusive to the ChaC family (forming the active-site surface) are required for structural stability. Validation was performed by in silico docking, MD simulations, MMGBSA binding energy, and in vivo yeast activity assays with point mutants. Molecular docking of glutathione with modeled hChaC1, MD simulations, MMGBSA binding energy calculations, yeast in vivo activity assays of site-directed mutants Proteins Medium 36456186
2022 DJ-1 (PARK7) binds the basic leucine zipper domain of ATF3 (shown by bimolecular fluorescence complementation) and inhibits ATF3 binding to the CHAC1 promoter, thereby downregulating CHAC1 expression and reducing glutathione degradation in astrocytes. DJ-1 knockout significantly upregulated CHAC1. DJ-1 knockout, high-throughput sequencing, bimolecular fluorescence complementation (BiFC) for DJ-1–ATF3 interaction, promoter-binding assay, GSH measurement Neuroscience research Medium 35988816
2023 MIA3 binds directly to CHAC1 protein (co-immunoprecipitation and confocal co-localization) and promotes CHAC1 expression and glutathione degradation, thereby promoting hepatocellular carcinoma cell growth and metastasis. MIA3 knockout reduced CHAC1 expression and slowed GSH degradation. Co-immunoprecipitation, confocal microscopy, MIA3 overexpression/knockout, RNA-seq, GSH measurement, cell proliferation/migration/invasion assays Molecular and cellular biochemistry Medium 37948019
2023 CHAC1 inactivation via CRISPR/Cas9 knock-in of an enzyme-inactivating mutation preserved muscle glutathione levels under fasting, cancer cachexia, and chemotherapy conditions, but failed to prevent muscle wasting, demonstrating that glutathione preservation alone is insufficient to protect against cachexia-induced muscle loss. CRISPR/Cas9 knock-in of enzymatic-inactivating mutation in mice, glutathione measurement, muscle wasting phenotypic analysis under multiple cachexia models PloS one Medium 37014882
2024 CHAC1 acts as a bridge connecting UBA2 and PKM2, enhancing SUMOylation of PKM2. SUMOylated PKM2 translocates from cytoplasm to nucleus, activating glycolysis-related gene expression and the Warburg effect in lung adenocarcinoma cells. E2F Transcription Factor 1 was identified as a transcriptional activator of CHAC1 by directly binding the CHAC1 promoter. Shotgun mass spectrometry-based proteomics, RNA-seq, co-IP for UBA2-CHAC1-PKM2 complex, SUMOylation assays, nuclear/cytoplasmic fractionation, ChIP for E2F1 at CHAC1 promoter, CHAC1 overexpression/knockdown in vitro and in vivo Cell death & disease Medium 39368995
2025 ATF4 directly binds the CHAC1 promoter (ChIP-seq and ChIP-qPCR) in renal tubular cells; ATF4 depletion inhibited CHAC1 upregulation and pro-ferroptotic responses induced by oxalate, establishing ATF4 as the direct transcriptional activator of CHAC1 in the ER stress-dependent ferroptosis pathway in calcium oxalate kidney stone models. ChIP-seq, ChIP-qPCR, ATF4 siRNA knockdown, 4-PBA (ER stress inhibitor) treatment, CHAC1 knockout, GSH/lipid peroxidation/Fe2+ measurements in vivo and in vitro Advanced science High 39836526
2025 CHAC1 haploinsufficiency (Chac1+/− mice) conferred resilience to kidney disease (folic acid nephropathy, adenine-induced CKD, diabetic nephropathy). Tubule cells from Chac1+/− mice showed increased glutathione, decreased lipid peroxidation, improved viability, and protection against ferroptosis, establishing CHAC1 as a mediator of kidney disease through glutathione degradation and ferroptosis. CRISPR-generated Chac1+/− mice, multiple kidney disease models, primary tubule cell isolation, GSH measurement, lipid peroxidation assays, ferroptosis gene expression analysis, correlation with kidney biopsy protein data Science translational medicine High 40267214
2025 The transcription factor BACH1 activates the CHAC1 promoter (dual-luciferase assay). BACH1 silencing attenuated ferroptosis by suppressing CHAC1 and restoring the GSH-GPX4 axis in cardiomyocytes. CHAC1 overexpression depleted GSH, suppressed GPX4, and enhanced lipid peroxidation during myocardial ischemia-reperfusion, while CHAC1 knockdown was partially protective; in vivo AAV-mediated CHAC1 overexpression worsened cardiac dysfunction and enlarged infarct area. Dual-luciferase promoter assay for BACH1-CHAC1, BACH1 siRNA, CHAC1 overexpression/knockdown, AAV-mediated cardiac CHAC1 overexpression in mice, GSH/GPX4/lipid peroxidation assays Antioxidants Medium 41750596
2025 GDIL lncRNA binds and relocalizes the nuclear exoribonuclease XRN2 to the cytoplasm, where GDIL serves as a scaffold for XRN2 to identify and degrade CHAC1 mRNA, thereby reducing CHAC1 protein levels, boosting GSH, and promoting platinum resistance in colorectal cancer. RNA pulldown, GDIL-XRN2 interaction assays, metabolomic and metabolic flux analysis, CHAC1 mRNA stability assays, antisense oligonucleotide suppression in cell lines and patient-derived xenografts Cell death & disease Medium 39893168
2024 m6A methylation by METTL3/14 destabilizes CHAC1 mRNA via YTHDF2-mediated decay (RIP assays confirmed METTL3/YTHDF2-CHAC1 mRNA interaction). Arsenic treatment reduced METTL3/14 expression, inhibited m6A modification of CHAC1 mRNA, and increased CHAC1 mRNA half-life (~2-fold), leading to elevated CHAC1 protein, glutathione degradation, GPX4 suppression, and β-cell ferroptosis. METTL3 overexpression restored CHAC1 mRNA degradation and alleviated arsenic-induced dysfunction. MeRIP (m6A sequencing), RIP assay, METTL3/14 overexpression, CHAC1 mRNA half-life measurement (actinomycin D), CHAC1 knockdown, GSH/GPX4/ferroptosis assays Ecotoxicology and environmental safety Medium 39667319
2025 NUPR1 physically interacts with ATF4 (co-immunoprecipitation in HK2 cells) and suppresses ferroptosis in renal ischemia-reperfusion injury by inhibiting the ATF4-CHAC1 pathway; NUPR1 overexpression reduced CHAC1 expression while NUPR1 knockdown enhanced ferroptosis via ATF4-CHAC1 activation. Co-immunoprecipitation (NUPR1–ATF4), NUPR1 overexpression/knockdown, renal IRI mouse model, hypoxia-reoxygenation HK2 cell model, ferroptosis marker measurement Cellular signalling Medium 42019644
2025 H3K9 acetylation at the CHAC1 promoter (mediated by increased histone acetyltransferase P300) is required for DHA-induced transcriptional upregulation of CHAC1 in hepatic stellate cells. ATF4 binds two essential CHAC1 promoter regions (-212 to -199 bp and -269 to -257 bp), confirmed by luciferase reporter assays and ChIP-qPCR; inhibiting histone acetylation or ATF4 both blocked CHAC1 induction and reduced ferroptosis. ChIP-qPCR for H3K9ac and ATF4, luciferase reporter with WT and mutated CHAC1 promoter, P300 inhibition, ATF4 knockdown, RNA-seq, in vivo CCl4 fibrosis model Chinese medical journal Medium 40947783
2025 EGR1 transcriptionally activates CHAC1 expression; EGR1 binding to the CHAC1 promoter was validated by chromatin immunoprecipitation and dual-luciferase reporter assays. EGR1-driven CHAC1 upregulation promotes ferroptosis in keratinocytes; caffeic acid inhibits ferroptosis by suppressing the EGR1-CHAC1 axis. ChIP assay, dual-luciferase reporter assay, EGR1/CHAC1 overexpression and knockdown plasmids, ferroptosis markers (MDA, ROS, Fe2+, GSH), flow cytometry Current molecular medicine Medium 39129295
2024 Juglone (a naturally occurring naphthoquinone) inhibits ChaC1 enzymatic activity with an IC50 of 8.7 µM in vitro; inhibition is non-competitive with glutathione and occurs through a novel mechanism independent of cysteine adduct formation (a cysteine-free ChaC1 variant was still inhibited). Plumbagin was also identified as an effective inhibitor. Yeast-based high-throughput functional screens, in vitro ChaC1 enzymatic assays, kinetic studies (competitive vs. non-competitive), cysteine-free ChaC1 variant testing The Biochemical journal Medium 39400295
2025 CHAC1 promotes ferroptosis in sepsis-exposed cardiomyocytes via the ATF4-CHOP-CHAC1 axis. miR-383-3p directly targets ATF4 mRNA (validated by dual-luciferase assay), thereby suppressing the ATF4-CHOP-CHAC1 pathway; ATF4 overexpression abolished miR-383-3p's protective effects, and ATF4 knockdown phenocopied miR-383-3p suppression of CHAC1 and ferroptosis. Dual-luciferase reporter assay (miR-383-3p–ATF4), ATF4 overexpression/knockdown, LPS cardiomyocyte model, miR-383-3p mimics/inhibitors, in vivo sepsis mouse model, ferroptosis markers Cellular signalling Medium 41093083

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. Journal of immunology (Baltimore, Md. : 1950) 275 19109178
2017 CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway. Oncotarget 245 29383104
2012 Nisin, an apoptogenic bacteriocin and food preservative, attenuates HNSCC tumorigenesis via CHAC1. Cancer medicine 186 23342279
2012 Mammalian proapoptotic factor ChaC1 and its homologues function as γ-glutamyl cyclotransferases acting specifically on glutathione. EMBO reports 175 23070364
2019 Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in Burkitt's Lymphoma. Biochemical and biophysical research communications 173 31537387
2015 Human CHAC1 Protein Degrades Glutathione, and mRNA Induction Is Regulated by the Transcription Factors ATF4 and ATF3 and a Bipartite ATF/CRE Regulatory Element. The Journal of biological chemistry 167 25931127
2023 Anti-CHAC1 exosomes for nose-to-brain delivery of miR-760-3p in cerebral ischemia/reperfusion injury mice inhibiting neuron ferroptosis. Journal of nanobiotechnology 146 36967397
2021 Dihydroartemisinin triggers ferroptosis in primary liver cancer cells by promoting and unfolded protein response‑induced upregulation of CHAC1 expression. Oncology reports 78 34558645
2011 Elevated mRNA expression of CHAC1 splicing variants is associated with poor outcome for breast and ovarian cancer patients. British journal of cancer 63 22108517
2022 Ferroptosis-related gene NOX4, CHAC1 and HIF1A are valid biomarkers for stomach adenocarcinoma. Journal of cellular and molecular medicine 57 35023280
2024 CHAC1: a master regulator of oxidative stress and ferroptosis in human diseases and cancers. Frontiers in cell and developmental biology 53 39534397
2024 Cancer associated fibroblast secreted miR-432-5p targets CHAC1 to inhibit ferroptosis and promote acquired chemoresistance in prostate cancer. Oncogene 52 38769193
2021 Crosstalk between Endoplasmic Reticulum Stress and Oxidative Stress in Heat Exposure-Induced Apoptosis Is Dependent on the ATF4-CHOP-CHAC1 Signal Pathway in IPEC-J2 Cells. Journal of agricultural and food chemistry 50 34919378
2023 CHAC1 as a Novel Contributor of Ferroptosis in Retinal Pigment Epithelial Cells with Oxidative Damage. International journal of molecular sciences 48 36675091
2016 The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity. Neuropharmacology 45 27986595
2022 Sevoflurane Induces Ferroptosis of Glioma Cells Through Activating the ATF4-CHAC1 Pathway. Frontiers in oncology 44 35372041
2020 Inhibiting Rab27a in renal tubular epithelial cells attenuates the inflammation of diabetic kidney disease through the miR-26a-5p/CHAC1/NF-kB pathway. Life sciences 41 32853650
2025 CHAC1 Mediates Endoplasmic Reticulum Stress-Dependent Ferroptosis in Calcium Oxalate Kidney Stone Formation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 33 39836526
2018 Helicobacter pylori induces somatic mutations in TP53 via overexpression of CHAC1 in infected gastric epithelial cells. FEBS open bio 29 29632819
2025 CNPY2 Aggravates Renal Tubular Cell Ferroptosis in Diabetic Nephropathy by Regulating PERK/ATF4/CHAC1 Pathway and MAM Integrity. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 28 40211809
2022 Glaucocalyxin A impairs tumor growth via amplification of the ATF4/CHOP/CHAC1 cascade in human oral squamous cell carcinoma. Journal of ethnopharmacology 26 35151835
2021 Metformin inhibits gastric cancer cell proliferation by regulation of a novel Loc100506691-CHAC1 axis. Molecular therapy oncolytics 26 34514098
2018 CHAC1 Is Differentially Expressed in Normal and Cystic Fibrosis Bronchial Epithelial Cells and Regulates the Inflammatory Response Induced by Pseudomonas aeruginosa. Frontiers in immunology 25 30555487
2023 CHAC1 exacerbates LPS-induced ferroptosis and apoptosis in HK-2 cells by promoting oxidative stress. Allergologia et immunopathologia 22 36916093
2024 Brusatol hinders the progression of bladder cancer by Chac1/Nrf2/SLC7A11 pathway. Experimental cell research 21 38663476
2023 ALKBH5-mediated CHAC1 depletion promotes malignant progression and decreases cisplatin-induced oxidative stress in gastric cancer. Cancer cell international 21 38007439
2019 Higher expression of cation transport regulator-like protein 1 (CHAC1) predicts of poor outcomes in uveal melanoma (UM) patients. International ophthalmology 21 31161335
2020 Transcriptional Activation of Chac1 and Other Atf4-Target Genes Induced by Extracellular l-Serine Depletion is negated with Glycine Consumption in Hepa1-6 Hepatocarcinoma Cells. Nutrients 20 33023086
2016 TRIB3 increases cell resistance to arsenite toxicity by limiting the expression of the glutathione-degrading enzyme CHAC1. Biochimica et biophysica acta 17 27526673
2023 CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia. PloS one 16 37014882
2019 CHAC1 overexpression in human gastric parietal cells with Helicobacter pylori infection in the secretory canaliculi. Helicobacter 16 31111570
2022 High levels of unfolded protein response component CHAC1 associates with cancer progression signatures in malignant breast cancer tissues. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 14 35930144
2019 The glutathione degrading enzyme, Chac1, is required for calcium signaling in developing zebrafish: redox as an upstream activator of calcium. The Biochemical journal 14 31189567
2023 CHAC1 promotes cell ferroptosis and enhances radiation sensitivity in thyroid carcinoma. Neoplasma 13 38247333
2025 Long noncoding RNA GDIL acts as a scaffold for CHAC1 and XRN2 to promote platinum resistance of colorectal cancer through inhibition of glutathione degradation. Cell death & disease 12 39893168
2024 Whole transcriptome profiling reveals a lncMDP1 that regulates myogenesis by adsorbing miR-301a-5p targeting CHAC1. Communications biology 12 38698103
2024 Hederagenin promotes lung cancer cell death by activating CHAC1-dependent ferroptosis pathway. Biochemical and biophysical research communications 12 38735142
2023 MIA3 promotes the degradation of GSH (glutathione) by binding to CHAC1, thereby promoting the progression of hepatocellular carcinoma. Molecular and cellular biochemistry 12 37948019
2025 Perfluorooctane sulfonate mediates GSH degradation leading to oral keratinocytes ferroptosis and mucositis through activation of the ER stress-ATF4-CHAC1 axis. Ecotoxicology and environmental safety 11 40037075
2024 CHAC1 blockade suppresses progression of lung adenocarcinoma by interfering with glucose metabolism via hijacking PKM2 nuclear translocation. Cell death & disease 11 39368995
2022 DJ-1 inhibits glutathione degradation by downregulating CHAC1 expression in astrocytes. Neuroscience research 10 35988816
2025 Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) increases kidney disease risk by modulating ferroptosis. Science translational medicine 9 40267214
2022 CHAC1 as a novel biomarker for distinguishing alopecia from other dermatological diseases and determining its severity. IET systems biology 8 35983595
2024 Protein folding dependence on selenoprotein M contributes to steady cartilage extracellular matrix repressing ferroptosis via PERK/ATF4/CHAC1 axis. Osteoarthritis and cartilage 7 39419437
2020 Characterization of the 5'-flanking region of the human and mouse CHAC1 genes. Biochemistry and biophysics reports 7 33102815
2022 The ChaC1 active site: Defining the residues and determining the role of ChaC1-exclusive residues in the structural and functional stability. Proteins 6 36456186
2025 MiR-383-3p attenuates sepsis-induced myocardial ferroptosis by targeting ATF4 and inhibiting the ATF4-CHOP-CHAC1 signaling axis. Cellular signalling 5 41093083
2025 Caffeic Acid Reduces Ferroptosis to Dampen Inflammation of Keratinocytes in Psoriasis by Inhibiting EGR1-induced Transcription Activation of CHAC1. Current molecular medicine 4 39129295
2023 CHAC1 exacerbates arsenite cytotoxicity by lowering intracellular glutathione levels. The Journal of toxicological sciences 4 37661365
2024 Arsenic inducible islet β-cell dysfunction and ferroptosis through m6A-YTHDF2-dependent CHAC1 enhancement. Ecotoxicology and environmental safety 3 39667319
2025 Nootkatone inhibits the progression of glioblastoma by activating the ATF4-CHOP-CHAC1 pathway. Molecular medicine (Cambridge, Mass.) 2 39819316
2025 Vitamin D3 and its active form calcitriol suppress erythroleukemia through upregulation of CHAC1 and downregulation of NOTCH1. Medical oncology (Northwood, London, England) 2 40146328
2025 Dot1l Regulates the Spontaneous Bone Regeneration of Periosteum-Derived Stem Cells by Regulating Chac1 Expression. Stem cells international 2 40677859
2025 Paliperidone Inhibits Ferroptosis Mediated by Autophagy in Renal Tubular Epithelial Cells by Targeting CHAC1. Advanced biology 1 40259582
2025 Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer. Redox biology 1 40460553
2025 Characterization of Ferroptosis-Associated Subtypes in Psoriasis and the Potential of CHAC1 as a Diagnostic Biomarker Based on Machine Learning. Clinical, cosmetic and investigational dermatology 1 41357319
2026 Mechanism of Saikosaponin D in regulating ferroptosis in patient-derived lung adenocarcinoma organoids via upregulation of ATF3/CHOP/CHAC1 signaling. Scientific reports 0 41620478
2026 BACH1-CHAC1-Glutathione Axis Aggravates Myocardial Ischemia-Reperfusion Injury by Enhancing Ferroptosis and Oxidative Stress. Antioxidants (Basel, Switzerland) 0 41750596
2026 NUPR1 alleviates renal ischemia reperfusion injury by inhibiting ferroptosis involving the ATF4-CHAC1 pathway. Cellular signalling 0 42019644
2026 Chac1 deficiency confers sepsis resistance by enriching gut microbiota-derived indole-3-carboxylic acid to drive macrophage metabolic shifts. Journal of advanced research 0 42049093
2026 EIF2α-ATF4-CHAC1 Signalling Links ER Stress to Ferroptosis in Human Aortic Smooth Muscle Cells: Mechanistic Insights and Therapeutic Implications. Journal of cellular and molecular medicine 0 42068228
2025 CHAC1 in urological tumors: contextual dualism and therapeutic implications. Frontiers in oncology 0 40860820
2025 Verbascoside inhibits OGD/R-induced SK-N-SH cell injury by regulating METTL14/CHAC1/NRF2/SLC7A11/GPX4 pathway. Brain research bulletin 0 40935194
2025 H3K9 acetylation-dependent CHAC1 transcription in dihydroartemisinin-induced hepatic stellate cell ferroptosis. Chinese medical journal 0 40947783
2025 ATF3 enhancement of CHAC1 expression: A pathway to neuronal ferroptosis in spinal cord injury. Brain research bulletin 0 41046987
2025 Shengqing Jiangzhuo Capsule Alleviates Intestinal Inflammation in Chronic Kidney Disease by Downregulating CHAC1 to Inactivate the HIF-1 Pathway. Mediators of inflammation 0 41245353
2025 ChaC1-based drug screenings identify a synergistic lethal effect of auranofin and proteasome inhibitors in hepatocellular carcinoma cells. Cell death discovery 0 41249117
2024 Identification of inhibitors of human ChaC1, a cytoplasmic glutathione degrading enzyme through high throughput screens in yeast. The Biochemical journal 0 39400295

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