biostudies-literatureUnknown32(9)Chen ZTumor 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. Cell death and differentiation1679-1690https://www.ebi.ac.uk/biostudies/studies/S-EPMC12432198biostudies-literatureGCLC desuccinylation regulated by oxidative stress protects human cancer cells from ferroptosis.PMC12432198Chen ZZhang JWei DNiu KWang JLi MZhao YDeng YfalseGCLC desuccinylation regulated by oxidative stress protects human cancer cells from ferroptosis.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. 2025-01-01T00:00:00Z2025 Sep2026-06-02T08:48:08.881Z2026-04-16T03:12:39.909ZS-EPMC124321984018819610.1038/s41418-025-01505-8