ArticleCell death and differentiation2025
GCLC desuccinylation regulated by oxidative stress protects human cancer cells from ferroptosis.
Article in Cell death and differentiation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Time-Dependent Changes in Salivary Antioxidants After 5-ALA Photodynamic Therapy vs. Clobetasol in Oral Lichen Planus: A Randomized Clinical Trial.International journal of molecular sciences · 2025Trial
- Spatial Transcriptomics Reveals a T Cell-Mediated Microglial Activation Axis of Immune Checkpoint Inhibition-Related Adverse Events in the Brain.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Exogenous N-Acetyl-L-cysteine Improves Soybean Saline-Alkali Tolerance by Enhancing the hGSH Pathway to Alleviate Oxidative Damage.Plants (Basel, Switzerland) · 2026Article
- Recurrent PIK3CA-E545K mutation promotes cervical cancer growth and invasion via AKT/mTOR signaling.Molecular genetics and genomics : MGG · 2026Article
- Vitamin E-Related Molecular Signatures in Adolescent Idiopathic Scoliosis: A Hypothesis-Generating Multi-Omics Analysis.Food science & nutrition · 2026Article
- G3BP1 Succinylation at K413 is Critical for Cardiac Function by Modulating PI3K-AKT-mTOR Signal Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The biphasic interactions between ferroptosis and oxidative stress: from molecular mechanisms to disease interventions.Molecular biology reports · 2026Review
- Tipping the balance: NRF2's dual role in ferroptotic fate.Oncogenesis · 2026Review
- Hesperetin-7-O-Glucuronide Improves Endothelial Cell Function Through Improving NO/ET-1 Balance and Reducing Oxidative Stress via miRNAs.Current issues in molecular biology · 2026Article
- Article
- Glutamate-cysteine ligase catalytic related glutathione metabolism inhibited high mobility group box 1 release by regulating epithelium ferroptosis in asthma.Journal of thoracic disease · 2026Article
- AQP7 Protects Vitrified Sheep GV-Stage Oocyte Maturation via Mitochondrial Activity.Animals : an open access journal from MDPI · 2026Article
- QAL333's antitumor activity and predictive modeling: integrated transcriptomic-bioinformatic analysis reveals selective cytotoxicity and sensitivity determinants.Scientific reports · 2026Article
- Succinylation in cancer immunotherapy: mechanisms, biomarkers, and therapeutic implications.Frontiers in immunology · 2026Review
- Ferroptosis regulatory networks and precision interventions in autoimmune hepatitis: comparison with cholestatic diseases.Frontiers in immunology · 2026Review
- Emerging Role of Sirtuins-Mediated Ferroptosis in Hepatocellular Carcinoma Progression: Mechanisms and Therapeutic Perspectives.Journal of hepatocellular carcinoma · 2026Review
- Effects of aging and anti-aging dietary restriction on regulators of the [NADPH]/[NADPFree radical biology & medicine · 2025Review
- The metabolic-epigenetic interface: lysine succinylation orchestrates bidirectional crosstalk in neurodegenerative disorders.Frontiers in neurology · 2025Review
- Glutathione-ROS pathway activation by probiotic B240 augments macrophage response to influenza.Frontiers in cellular and infection microbiology · 2025Article
- Ferroptosis in the tumor microenvironment: mechanisms, advances, and therapeutic perspectives.Frontiers in oncology · 2025Review
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Authors and funding
8 authors.
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Abstract
Tumor cells evolve strong antioxidant capacities to counteract the abnormal high level of reactive oxygen species (ROS) in the tumor microenvironment. Glutamate-cysteine ligase catalyzing subunit (GCLC) for synthesis of antioxidant glutathione (GSH) represents the key enzyme to maintain redox homeostasis of tumor cells, however, whether its activity is regulated by posttranslational modifications, such as succinylation, remains to be clarified. Here, we demonstrate the existence of succinylation modification on GCLC by in vitro and in vivo assays. NAD-dependent deacetylase Sirtuin-2 (SIRT2) serves as the desuccinylase and catalyzes GCLC desuccinylation at sites of K38, K126, and K326. Specifically, GCLC directly interacts with SIRT2, which can be substantially enhanced upon ROS treatment. This strengthened association results in GCLC desuccinylation and activation, consequently promoting GSH synthesis and rendering cancer cells resistant to ferroptosis induction. Depletion of SIRT2 decreases total GSH level and meanwhile increases the cellular susceptibility to ferroptosis, which can mostly be rescued by introducing wild-type GCLC, but not its 3K-E mutant. We further demonstrated that histone acetyltransferase P300 serves as the succinyltransferase of GCLC, and their association is remarkably decreased after ROS treatment. Thus, SIRT2-regulated GCLC succinylation represents an essential signaling axis for cancer cells to maintain their redox balance in coping with oxidative stress-induced ferroptosis.
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