Affinage

CHAC1

Glutathione-specific gamma-glutamylcyclotransferase 1 · UniProt Q9BUX1

Length
222 aa
Mass
24.4 kDa
Annotated
2026-04-28
66 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHAC1 is a cytosolic γ-glutamyl cyclotransferase that specifically degrades glutathione, functioning as the first eukaryotic intracellular glutathione-degrading enzyme and a critical effector linking endoplasmic reticulum stress signaling to oxidative cell death. Its enzymatic activity, dependent on defined active-site residues including E115, depletes cellular glutathione, elevates reactive oxygen species, and promotes ferroptosis and apoptosis in diverse tissues including kidney, heart, brain, and multiple cancer types (PMID:23070364, PMID:31189567, PMID:40267214, PMID:37014882). CHAC1 transcription is directly activated by ATF4 through bipartite ATF/CRE promoter elements (with contributions from ATF3, BACH1, EGR1, and epigenetic regulation via H3K9 acetylation) and is negatively regulated at the mRNA level by m6A-dependent decay and specific microRNAs (PMID:25931127, PMID:40947783, PMID:39667319, PMID:38769193). Beyond its catalytic role, CHAC1 functions non-enzymatically as a scaffold bridging UBA2 and PKM2 to promote PKM2 SUMOylation and nuclear translocation, thereby activating glycolysis-related gene expression (PMID:39368995).

Mechanistic history

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

    Establishing CHAC1 as a stress-responsive proapoptotic gene resolved how the ATF4-ATF3-CHOP arm of the UPR executes cell death through a previously uncharacterized downstream effector.

    Evidence siRNA knockdown and overexpression with TUNEL, PARP cleavage, and AIF translocation assays in human aortic endothelial cells

    PMID:19109178

    Open questions at the time
    • Enzymatic activity of CHAC1 was unknown
    • Direct transcription factor binding to the CHAC1 promoter was not demonstrated
    • Mechanism of apoptosis induction was undefined
  2. 2012 High

    Identifying CHAC1 as a γ-glutamyl cyclotransferase that specifically degrades glutathione — the first such cytosolic enzyme in eukaryotes — provided the molecular mechanism for its proapoptotic function and established GSH depletion as the proximal biochemical event.

    Evidence In vitro enzyme assays with catalytic-dead E>Q mutant and in vivo yeast functional validation

    PMID:23070364

    Open questions at the time
    • How CHAC1 transcription is regulated at the promoter level was not resolved
    • Whether glutathione degradation connects to specific regulated cell death pathways (ferroptosis) was unknown
    • Structural basis of substrate specificity was not determined
  3. 2015 High

    Mapping the CHAC1 promoter architecture revealed that ATF4 and ATF3 directly bind bipartite ATF/CRE and ACM elements, explaining how integrated stress response signaling converges on CHAC1 transcriptional activation.

    Evidence Luciferase reporter assays, EMSA, ChIP, and glutathione measurement with catalytic mutant in HEK293 cells

    PMID:25931127

    Open questions at the time
    • Role of additional transcription factors (CHOP, C/EBPβ) in fine-tuning CHAC1 was incompletely resolved
    • Epigenetic regulation of the CHAC1 promoter was not addressed
    • In vivo relevance of these promoter elements was not tested
  4. 2016 Medium

    Discovery of CHAC1 binding to Notch3 and negative regulation by TRIB3 expanded the functional repertoire beyond enzymatic GSH degradation, revealing both non-catalytic protein interactions and feedback control within the ATF4 pathway.

    Evidence Co-immunoprecipitation of CHAC1-Notch3 in glioma cells; Trib3-KO MEFs with Chac1 siRNA rescue and GSH/cell death readouts

    PMID:27526673 PMID:27986595

    Open questions at the time
    • CHAC1-Notch3 interaction lacks reciprocal validation and structural characterization
    • Whether TRIB3 regulation of CHAC1 is direct or indirect at the promoter level was not fully determined
    • Generalizability of Notch3 interaction beyond glioma was not tested
  5. 2017 Medium

    Linking CHAC1-mediated GSH depletion to ferroptosis and necroptosis during cystine starvation established CHAC1 as a key effector of non-apoptotic cell death, broadening its role beyond classical apoptosis.

    Evidence siRNA knockdown with GSH measurement and RIP1/MLKL inhibitor rescue in triple-negative breast cancer cells

    PMID:29383104

    Open questions at the time
    • Whether CHAC1 is required for ferroptosis in non-cancer physiological contexts was not tested
    • Relative contribution of CHAC1 versus system Xc− loss to GSH depletion during cystine starvation was not quantified
  6. 2019 High

    Demonstrating that CHAC1-dependent glutathione degradation is an upstream activator of calcium signaling during zebrafish embryogenesis revealed an unexpected developmental function and mechanistically coupled redox state to calcium transients in vivo.

    Evidence Zebrafish morpholino knockdown with rescue by WT but not catalytic-dead Chac1, live Grx1-roGFP2 redox imaging and GCaMP6s calcium imaging

    PMID:31189567

    Open questions at the time
    • Molecular mechanism linking GSH oxidation to calcium channel/store activation was not identified
    • Whether this calcium-signaling function operates in mammalian systems was not tested
  7. 2020 Medium

    Identification of CHOP as an indirect transcriptional repressor of CHAC1, DJ-1 as a suppressor of ATF3-mediated CHAC1 induction, and miR-26a-5p as a post-transcriptional regulator revealed multiple layers of negative regulation that restrain CHAC1 activity.

    Evidence EMSA/reporter assays for CHOP; BiFC for DJ-1/ATF3 interaction with ChIP; miR-26a-5p 3′-UTR targeting and CHAC1-KO rescue in renal cells

    PMID:32853650 PMID:33102815 PMID:35988816

    Open questions at the time
    • Mechanism of CHOP indirect repression was not defined
    • DJ-1/ATF3 interaction was shown by BiFC only — not independently validated by orthogonal method
    • In vivo significance of miR-26a-5p regulation was not established
  8. 2022 Medium

    Structural mapping of ChaC1 active-site residues mediating glutathione binding provided the first substrate-enzyme interaction model and identified ChaC-family-exclusive residues essential for catalytic activity.

    Evidence Molecular docking, MD simulations, MMGBSA calculations validated by in vivo yeast mutant assays

    PMID:36456186

    Open questions at the time
    • No experimental crystal structure of ChaC1 with bound substrate exists
    • Whether these residues are druggable was not assessed
  9. 2023 High

    CRISPR knock-in of a catalytic-inactivating mutation in mice demonstrated that CHAC1 enzymatic activity is required for stress-induced muscle glutathione depletion but is insufficient alone to prevent muscle wasting, dissociating GSH preservation from anti-atrophic benefit.

    Evidence CRISPR/Cas9 enzyme-inactivating knock-in across fasting, cachexia, and chemotherapy mouse models with GSH and muscle mass measurements

    PMID:37014882

    Open questions at the time
    • Whether CHAC1 inactivation protects other tissues (kidney, heart) in vivo was not tested in this model
    • Compensatory mechanisms for GSH degradation in muscle were not investigated
  10. 2024 Medium

    Discovery of a non-enzymatic scaffolding function — bridging UBA2 and PKM2 to promote PKM2 SUMOylation and nuclear translocation for glycolytic gene activation — revealed that CHAC1 influences tumor metabolism independently of its γ-glutamyl cyclotransferase activity.

    Evidence Shotgun mass spectrometry interactome, co-immunoprecipitation, SUMOylation assays, nuclear fractionation in lung adenocarcinoma cells

    PMID:39368995

    Open questions at the time
    • Whether this scaffolding function requires specific CHAC1 domains distinct from the active site is unknown
    • Independence from catalytic activity was not tested with enzyme-dead mutant
    • Single-lab observation awaits independent replication
  11. 2024 High

    Identification of juglone as a first-in-class non-competitive ChaC1 inhibitor (IC50 8.7 µM) through high-throughput screening provided both a pharmacological tool and evidence for a regulatory site outside the catalytic center.

    Evidence Yeast-based HTS, in vitro kinetic analysis, cysteine-free ChaC1 variant testing

    PMID:39400295

    Open questions at the time
    • Juglone binding site on ChaC1 is unknown
    • Selectivity profile against related enzymes and in vivo efficacy were not determined
    • Whether juglone inhibits ChaC2 was not tested
  12. 2025 High

    In vivo CRISPR haploinsufficiency across multiple kidney disease models and identification of additional transcriptional activators (BACH1, EGR1) and epigenetic regulators (H3K9ac/P300) established CHAC1 as a disease-relevant ferroptosis driver whose expression is controlled by a multi-layered transcriptional and epitranscriptomic regulatory network.

    Evidence Chac1 haploinsufficient mice in folic acid, adenine CKD, and diabetic nephropathy models with ChIP-seq; BACH1/EGR1 ChIP and reporter assays; H3K9ac ChIP-qPCR with P300 inhibition; m6A-RIP for METTL3/YTHDF2 regulation

    PMID:39129295 PMID:39667319 PMID:40267214 PMID:40947783 PMID:41750596

    Open questions at the time
    • A comprehensive integrated model of how multiple transcription factors and epigenetic marks converge on the CHAC1 promoter simultaneously is lacking
    • Therapeutic benefit of pharmacological CHAC1 inhibition in disease models has not been demonstrated
    • Whether CHAC1 contributes to human Mendelian disease is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • No experimental three-dimensional structure of human CHAC1 (apo or substrate-bound) has been determined, and the binding site and mechanism of the only known inhibitor (juglone) remain undefined; whether the non-catalytic scaffolding functions are separable from enzymatic activity has not been resolved with domain/mutant analysis.
  • No crystal/cryo-EM structure
  • No selective, validated in vivo inhibitor
  • Catalytic vs. non-catalytic functions not genetically separated in mammalian systems

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 6 GO:0060090 molecular adaptor activity 1
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-5357801 Programmed Cell Death 7 R-HSA-1430728 Metabolism 5 R-HSA-8953897 Cellular responses to stimuli 5 R-HSA-74160 Gene expression (Transcription) 3
Partners
ATF3ATF4MIA3NOTCH3NUPR1PKM2TRIB3UBA2

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 CHAC1 is a proapoptotic component of the unfolded protein response, positioned downstream of the ATF4-ATF3-CHOP cascade; CHAC1 overexpression enhanced apoptosis (TUNEL, PARP cleavage, AIF nuclear translocation) while CHAC1 siRNA suppressed apoptosis in human aortic endothelial cells. siRNA knockdown, overexpression plasmids, TUNEL assay, PARP cleavage assay, AIF nuclear translocation, expression microarray Journal of immunology High 19109178
2012 ChaC1 (and its homologues) functions as a γ-glutamyl cyclotransferase that specifically degrades glutathione but not other γ-glutamyl peptides; overexpression of catalytically active (but not catalytically dead E>Q mutant) protein led to glutathione depletion and enhanced apoptosis in yeast, establishing CHAC1 as the first cytosolic glutathione-degrading enzyme in eukaryotes. In vivo yeast studies, novel in vitro enzyme assays, catalytic dead mutant (E>Q) analysis EMBO reports High 23070364
2015 Human CHAC1 promoter-driven transcription is regulated by ATF4 and ATF3 through two key cis elements: a -267 ATF/CRE site and a novel -248 ATF/CRE modifier (ACM) element; ATF4 and ATF3 (and C/EBPβ) bind the CHAC1 promoter near these elements; CHAC1 overexpression depletes glutathione in HEK293 cells, an effect abolished by a catalytic mutant. Luciferase reporter assays, mutation/deletion analysis, immunoblot-EMSA, ChIP, glutathione measurement, catalytic mutant overexpression The Journal of biological chemistry High 25931127
2016 In glioma cells treated with temozolomide (TMZ), CHAC1 expression is upregulated via the JNK1/c-JUN pathway through transcriptional control; CHAC1 physically binds to Notch3 protein and inhibits Notch3 activation and its downstream signaling, thereby contributing to TMZ-mediated cytotoxicity. Transcriptome microarray, bioinformatics, CHAC1 overexpression and knockdown, caspase-3/9 activation assay, PARP degradation, co-immunoprecipitation (CHAC1-Notch3 binding) Neuropharmacology Medium 27986595
2016 TRIB3, acting downstream of ATF4, represses CHAC1 expression to limit glutathione degradation; in Trib3-deficient cells, arsenite stress causes markedly elevated CHAC1 mRNA/protein, accelerated glutathione consumption, and increased cell death—all rescued by Chac1 silencing, identifying TRIB3 as a negative regulator of CHAC1 within the ATF4 pathway. Mouse embryonic fibroblasts, Trib3 KO, siRNA knockdown of Chac1, promoter analysis, glutathione measurement, cell death assays Biochimica et biophysica acta Medium 27526673
2017 CHAC1 degrades glutathione downstream of the GCN2-eIF2α-ATF4 pathway during cystine starvation; CHAC1 knockdown rescued GSH levels and prevented cystine-starvation-induced necroptosis and ferroptosis in triple-negative breast cancer cells. siRNA knockdown, GSH measurement, RIP1 inhibitor/MLKL inhibitor rescue, Western blot for eIF2α phosphorylation and ATF4 Oncotarget Medium 29383104
2018 CHAC1 overexpression in H. pylori-infected gastric epithelial cells degrades glutathione and causes ROS accumulation, leading to somatic TP53 mutations; a catalytically inactive CHAC1 mutant did not cause TP53 mutations, and CHAC1 siRNA prevented the H. pylori-induced high frequency of TP53 mutations. CHAC1 overexpression, catalytically inactive mutant, siRNA knockdown, TP53 mutation analysis, GSH/ROS measurement in AGS cells FEBS open bio Medium 29632819
2018 In bronchial epithelial cells, LPS-induced CHAC1 mRNA expression is PERK-independent and involves ATF4; CHAC1 knockdown with siRNA modulates inflammatory markers and NF-κB signaling in response to LPS and flagellin. siRNA knockdown of CHAC1, qRT-PCR, NF-κB signaling analysis, bronchial epithelial cell model (NCI-H292) Frontiers in immunology Medium 30555487
2019 Zebrafish Chac1 is a glutathione-degrading enzyme required for calcium signaling during embryonic development; chac1 morphants showed attenuated intracellular glutathione oxidation (Grx1-roGFP2) and strongly reduced calcium transients (GCaMP6s), and developmental defects could be rescued by WT but not catalytically inactive Chac1, establishing that Chac1-mediated glutathione degradation is an upstream activator of calcium signaling. Zebrafish morpholino knockdown, rescue with WT and catalytic mutant, live redox imaging (Grx1-roGFP2), calcium imaging (GCaMP6s), in vivo enzymatic activity assessment The Biochemical journal High 31189567
2020 DJ-1 (PARK7) inhibits glutathione degradation in astrocytes by binding the basic leucine zipper domain of ATF3 (shown by bimolecular fluorescence complementation), preventing ATF3 binding to the CHAC1 promoter and thereby reducing CHAC1 expression. High-throughput sequencing, bimolecular fluorescence complementation (BiFC) for DJ-1/ATF3 interaction, ChIP/promoter binding assay, DJ-1 knockout Neuroscience research Medium 35988816
2020 CHOP exerts a novel inhibitory effect on CHAC1 transcription through an upstream ATF/CRE motif via an indirect mechanism (CHOP does not directly bind the CHAC1 ATF/CRE as shown by IM-EMSA), while ATF4 directly binds these CHAC1 promoter sequences. Luciferase reporter assays, IM-EMSA, deletion/mutation analysis of human and mouse CHAC1 5'-flanking region Biochemistry and biophysics reports Medium 33102815
2020 miR-26a-5p targets the 3'-UTR of CHAC1 mRNA; in renal proximal tubular epithelial cells, retention of miR-26a-5p (by Rab27a knockout) inhibits CHAC1 expression and thereby suppresses NF-κB signaling and the inflammatory response. miR-26a-5p mimic/inhibitor, 3'-UTR targeting validation, CHAC1 knockout, NF-κB pathway analysis in HK-2 cells Life sciences Medium 32853650
2021 In heat-stressed intestinal epithelial cells (IPEC-J2), CHAC1 is downstream of the ATF4-CHOP signaling branch; CHAC1 knockdown attenuates heat-stress-induced glutathione reduction and cell apoptosis, placing CHAC1 as a functional effector of the ATF4-CHOP-CHAC1 axis in heat-induced ERS-oxidative stress crosstalk. Transcriptome sequencing, Western blotting, siRNA knockdown of CHAC1, GSH measurement, apoptosis assays (caspase-3, cytochrome c) in IPEC-J2 cells Journal of agricultural and food chemistry Medium 34919378
2022 The active site residues of human ChaC1 responsible for direct interactions with glutathione substrate were identified (residues 38-YGSL-41, D68, R72, E115, Y143) using enzyme-substrate docking and validated by in vivo yeast assays and MD simulations; ChaC family-exclusive residues maintain structural stability of the active site. In silico active site mapping (molecular docking), MD simulations, MMGBSA binding energy calculations, in vivo yeast functional assays with mutants Proteins Medium 36456186
2023 MIA3/TANGO1 binds to CHAC1 protein (shown by co-immunoprecipitation and confocal co-localization) and promotes CHAC1 expression and GSH degradation; MIA3 overexpression increases CHAC1 levels and promotes hepatocellular carcinoma growth and metastasis, while MIA3 knockout reduces CHAC1 expression and inhibits these processes. Co-immunoprecipitation, confocal microscopy, RNA-seq, MIA3 overexpression/knockout in HCC cells (Hep-G2, Huh7), GSH measurement Molecular and cellular biochemistry Medium 37948019
2023 ALKBH5 demethylase regulates CHAC1 mRNA stability via m6A demethylation; ALKBH5 silencing increases CHAC1 expression, elevates intracellular ROS levels, and increases chemotherapy sensitivity in gastric cancer cells. Transcriptome and m6A sequencing, ALKBH5 siRNA, ROS measurement, chemosensitivity assays Cancer cell international Medium 38007439
2023 CHAC1 inactivation via CRISPR/Cas9 knock-in of an enzyme-inactivating mutation preserves muscle glutathione levels under fasting, cancer cachexia, and chemotherapy conditions in mice; however, CHAC1 inactivation alone is insufficient to prevent muscle wasting, dissociating glutathione preservation from anti-atrophic benefit. CRISPR/Cas9 enzyme-inactivating knock-in, multiple mouse wasting models, GSH measurement, muscle mass phenotyping PloS one High 37014882
2024 CHAC1 acts as a bridge connecting UBA2 and PKM2, enhancing SUMOylation of PKM2; SUMOylated PKM2 translocates from cytoplasm to nucleus where it activates glycolysis-related genes, promoting the Warburg effect in lung adenocarcinoma cells. Shotgun mass spectrometry-based proteomics, RNA sequencing, co-immunoprecipitation, SUMOylation assays, nuclear/cytoplasmic fractionation, CHAC1 OE/KD functional studies Cell death & disease Medium 39368995
2024 CAF-derived exosomal miR-432-5p targets CHAC1 mRNA to reduce GSH consumption, inhibit ferroptosis, and increase docetaxel resistance in prostate cancer cells; suppression of CHAC1 by miR-432-5p reduces lipid ROS accumulation and prevents erastin-induced ferroptosis. Exosome isolation from CAFs, miR-432-5p functional studies, CHAC1 3'-UTR targeting, lipid ROS assay, erastin-induced ferroptosis model, GSH measurement Oncogene Medium 38769193
2024 Juglone (a naphthoquinone) is a first-in-class inhibitor of ChaC1 with IC50 of 8.7 µM identified through yeast-based high-throughput screening; inhibition is non-competitive with the glutathione substrate and persists in a cysteine-free ChaC1 variant, indicating a novel inhibitory mechanism not involving active-site cysteine adduction. High-throughput yeast-based screens, in vitro enzymatic assays, kinetic analysis, cysteine-free ChaC1 variant testing, IC50 determination The Biochemical journal High 39400295
2025 CHAC1 mediates kidney disease risk by degrading glutathione in tubular cells; Chac1 haploinsufficient mice (CRISPR-generated) showed increased GSH, decreased lipid peroxidation, and protection against ferroptosis across multiple kidney disease models (folic acid nephropathy, adenine CKD, diabetic nephropathy); ChIP-seq confirmed ATF4 as a direct transcriptional activator of CHAC1. CRISPR Chac1 haploinsufficiency, multiple in vivo kidney disease models, GSH/lipid peroxidation measurement, ferroptosis gene expression, ChIP-seq, human kidney biopsy correlation Science translational medicine High 40267214
2025 BACH1 transcription factor directly activates the CHAC1 promoter (shown by dual-luciferase assay); BACH1 silencing attenuates ferroptosis by suppressing CHAC1 and restoring GSH-GPX4 axis in cardiomyocytes during ischemia-reperfusion injury; CHAC1 overexpression (via AAV) worsened cardiac dysfunction and iron deposition in a mouse I/R model. Dual-luciferase promoter assay, BACH1 siRNA, CHAC1 AAV overexpression in vivo, RNA sequencing (OGD/R model), GSH/GPX4/lipid peroxidation measurement, mouse I/R model Antioxidants Medium 41750596
2025 EGR1 transcriptionally activates CHAC1; chromatin immunoprecipitation and dual-luciferase reporter assays confirmed direct EGR1 binding at the CHAC1 promoter; EGR1 overexpression potentiates ferroptosis in keratinocytes, an effect that is phenocopied by CHAC1 overexpression and reversed by EGR1 knockdown. ChIP, dual-luciferase reporter assay, EGR1/CHAC1 OE and KD, ferroptosis markers (MDA, ROS, Fe2+, GSH) in keratinocytes Current molecular medicine Medium 39129295
2025 lncRNA GDIL serves as a scaffold for XRN2 in the cytoplasm, directing XRN2 to degrade CHAC1 mRNA; GDIL promotes GSH accumulation by inhibiting CHAC1-mediated GSH degradation, thereby conferring platinum resistance in colorectal cancer. RNA pulldown, metabolomic and metabolic flux analysis, XRN2 relocalization study, CHAC1 mRNA stability assay, GDIL OE/KD in resistant cancer cells Cell death & disease Medium 39893168
2025 NUPR1 interacts with ATF4 (shown by immunoprecipitation in HK2 cells) and suppresses ferroptosis in renal ischemia-reperfusion injury by inhibiting the ATF4-CHAC1 pathway; NUPR1 overexpression reduces ATF4-driven CHAC1 transcription and subsequent glutathione depletion. Co-immunoprecipitation (NUPR1-ATF4), NUPR1 overexpression/knockdown, murine renal IRI model, HK2 hypoxia-reoxygenation model, ferroptosis marker assays Cellular signalling Medium 42019644
2025 H3K9 acetylation (mediated by histone acetyltransferase P300) at the CHAC1 promoter is required for ATF4-driven transcriptional upregulation of CHAC1 in hepatic stellate cells treated with DHA; luciferase assays with mutated CHAC1 promoter identified -212 to -199 bp and -269 to -257 bp as essential ATF4 binding regions; inhibiting histone acetylation blocked DHA-induced CHAC1 upregulation and ferroptosis. ChIP-qPCR for H3K9 acetylation, luciferase reporter assay with WT and mutated CHAC1 promoter, P300 inhibition, RNA sequencing, in vivo CCl4 liver fibrosis model Chinese medical journal Medium 40947783
2024 Arsenic inhibits METTL3/14-mediated m6A modification of CHAC1 mRNA, reducing YTHDF2-mediated degradation of CHAC1 mRNA and thereby increasing CHAC1 expression; RIP assays confirmed arsenic inhibits the interaction between METTL3/YTHDF2 and CHAC1 mRNA; METTL3 overexpression reduced CHAC1 mRNA half-life and ameliorated arsenic-induced ferroptosis in β-cells. m6A site identification, RIP assay (METTL3/YTHDF2-CHAC1 mRNA interaction), mRNA half-life measurement, METTL3 overexpression, CHAC1 KD in β-cells Ecotoxicology and environmental safety Medium 39667319

Source papers

Stage 0 corpus · 66 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) 272 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 240 29383104
2012 Nisin, an apoptogenic bacteriocin and food preservative, attenuates HNSCC tumorigenesis via CHAC1. Cancer medicine 185 23342279
2019 Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in Burkitt's Lymphoma. Biochemical and biophysical research communications 173 31537387
2012 Mammalian proapoptotic factor ChaC1 and its homologues function as γ-glutamyl cyclotransferases acting specifically on glutathione. EMBO reports 172 23070364
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 163 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 136 36967397
2021 Dihydroartemisinin triggers ferroptosis in primary liver cancer cells by promoting and unfolded protein response‑induced upregulation of CHAC1 expression. Oncology reports 76 34558645
2011 Elevated mRNA expression of CHAC1 splicing variants is associated with poor outcome for breast and ovarian cancer patients. British journal of cancer 61 22108517
2022 Ferroptosis-related gene NOX4, CHAC1 and HIF1A are valid biomarkers for stomach adenocarcinoma. Journal of cellular and molecular medicine 56 35023280
2024 Cancer associated fibroblast secreted miR-432-5p targets CHAC1 to inhibit ferroptosis and promote acquired chemoresistance in prostate cancer. Oncogene 49 38769193
2023 CHAC1 as a Novel Contributor of Ferroptosis in Retinal Pigment Epithelial Cells with Oxidative Damage. International journal of molecular sciences 48 36675091
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 48 34919378
2016 The CHAC1-inhibited Notch3 pathway is involved in temozolomide-induced glioma cytotoxicity. Neuropharmacology 45 27986595
2024 CHAC1: a master regulator of oxidative stress and ferroptosis in human diseases and cancers. Frontiers in cell and developmental biology 41 39534397
2022 Sevoflurane Induces Ferroptosis of Glioma Cells Through Activating the ATF4-CHAC1 Pathway. Frontiers in oncology 40 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 40 32853650
2018 Helicobacter pylori induces somatic mutations in TP53 via overexpression of CHAC1 in infected gastric epithelial cells. FEBS open bio 28 29632819
2021 Metformin inhibits gastric cancer cell proliferation by regulation of a novel Loc100506691-CHAC1 axis. Molecular therapy oncolytics 26 34514098
2022 Glaucocalyxin A impairs tumor growth via amplification of the ATF4/CHOP/CHAC1 cascade in human oral squamous cell carcinoma. Journal of ethnopharmacology 25 35151835
2025 CHAC1 Mediates Endoplasmic Reticulum Stress-Dependent Ferroptosis in Calcium Oxalate Kidney Stone Formation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 39836526
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) 23 40211809
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 23 30555487
2023 CHAC1 exacerbates LPS-induced ferroptosis and apoptosis in HK-2 cells by promoting oxidative stress. Allergologia et immunopathologia 21 36916093
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
2024 Brusatol hinders the progression of bladder cancer by Chac1/Nrf2/SLC7A11 pathway. Experimental cell research 19 38663476
2023 ALKBH5-mediated CHAC1 depletion promotes malignant progression and decreases cisplatin-induced oxidative stress in gastric cancer. Cancer cell international 19 38007439
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
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
2024 Whole transcriptome profiling reveals a lncMDP1 that regulates myogenesis by adsorbing miR-301a-5p targeting CHAC1. Communications biology 11 38698103
2024 CHAC1 blockade suppresses progression of lung adenocarcinoma by interfering with glucose metabolism via hijacking PKM2 nuclear translocation. Cell death & disease 10 39368995
2023 CHAC1 promotes cell ferroptosis and enhances radiation sensitivity in thyroid carcinoma. Neoplasma 10 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 9 39893168
2025 Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) increases kidney disease risk by modulating ferroptosis. Science translational medicine 9 40267214
2022 DJ-1 inhibits glutathione degradation by downregulating CHAC1 expression in astrocytes. Neuroscience research 9 35988816
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 8 40037075
2022 CHAC1 as a novel biomarker for distinguishing alopecia from other dermatological diseases and determining its severity. IET systems biology 8 35983595
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
2024 Protein folding dependence on selenoprotein M contributes to steady cartilage extracellular matrix repressing ferroptosis via PERK/ATF4/CHAC1 axis. Osteoarthritis and cartilage 5 39419437
2023 CHAC1 exacerbates arsenite cytotoxicity by lowering intracellular glutathione levels. The Journal of toxicological sciences 4 37661365
2025 Caffeic Acid Reduces Ferroptosis to Dampen Inflammation of Keratinocytes in Psoriasis by Inhibiting EGR1-induced Transcription Activation of CHAC1. Current molecular medicine 3 39129295
2024 Arsenic inducible islet β-cell dysfunction and ferroptosis through m6A-YTHDF2-dependent CHAC1 enhancement. Ecotoxicology and environmental safety 3 39667319
2025 MiR-383-3p attenuates sepsis-induced myocardial ferroptosis by targeting ATF4 and inhibiting the ATF4-CHOP-CHAC1 signaling axis. Cellular signalling 2 41093083
2025 Nootkatone inhibits the progression of glioblastoma by activating the ATF4-CHOP-CHAC1 pathway. Molecular medicine (Cambridge, Mass.) 1 39819316
2025 Vitamin D3 and its active form calcitriol suppress erythroleukemia through upregulation of CHAC1 and downregulation of NOTCH1. Medical oncology (Northwood, London, England) 1 40146328
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
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
2025 Dot1l Regulates the Spontaneous Bone Regeneration of Periosteum-Derived Stem Cells by Regulating Chac1 Expression. Stem cells international 0 40677859
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
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 0 41357319
2024 Identification of inhibitors of human ChaC1, a cytoplasmic glutathione degrading enzyme through high throughput screens in yeast. The Biochemical journal 0 39400295