Metabolic orchestration driven by GGCT: diverting glutamine to glutathione biosynthesis while enhancing glucose anaplerosis for tumor proliferation
Year: 2026
Type: article
Abstract: Glutamine (Gln) metabolism serves dual metabolic roles: it fuels the tricarboxylic acid (TCA) cycle, while concurrently sustaining redox balance through glutathione (GSH) synthesis. γ-Glutamylcyclotransferase (GGCT), a key metabolic enzyme frequently overexpressed in various cancers, has an undefined role in directing glutamine metabolic flux during tumorigenesis. This study demonstrated that glutamine promotes cancer cell growth by regulating GSH and reactive oxygen species (ROS) levels, with this process being closely associated with GGCT expression. Knockdown of GGCT significantly inhibited tumor growth, depleted GSH, and elevated ROS levels, whereas overexpression of GGCT exerted the opposite effects. Furthermore, we refined and established the Gln/c-Myc/miR-29b-3p/GGCT regulatory axis. Notably, GGCT knockdown markedly altered mitochondrial morphology and impaired oxidative phosphorylation and glycolysis capacity. Targeted metabolomics analysis revealed that GGCT knockdown significantly reduced the abundance of TCA cycle intermediates, while GGCT overexpression substantially increased their levels. [U- 13 C]glutamine isotope tracing experiments showed that GGCT overexpression reduced Gln contribution to the TCA cycle and diverted it preferentially to the GSH synthesis pathway for ROS regulation. In contrast, [U- 13 C]glucose isotope tracing results demonstrated a significant increase in TCA cycle intermediates derived from glucose when GGCT was overexpressed. Additional, supplementation of sodium pyruvate and JX06 in GGCT-knockdown cells confirmed that this regulatory effect of GGCT-mediated changes in ROS was independent of energy metabolism pathways. Collectively, this study identifies GGCT as a metabolic switch that diverts Gln flux toward GSH synthesis to maintain redox homeostasis, while enhancing glucose-fueled anaplerosis into the TCA cycle to sustain cell proliferation. These findings highlight GGCT as a potential therapeutic target for disrupting cancer redox adaptation and metabolic plasticity.
Source: Cell Death and Disease
Authors: Lijun Yang, Handi Sun, Ruonan Wang, Depeng Yang, Qi Gu, Guiping Zhao, Liping Sun, Xinghe Chen, Jianxin Lv, Xiaoyu Lin, Jiahui Cheng, Muhammad Luqman Akhtar, Mengmeng Zhang, Jingyu Zang, Xinyue Shi, Zihao Zhang, Lijun Deng, Lixing Xiao, Lei Yue, Wei Dong, Qinghua Jiang, Fang Han, Yu Li, Huan Nie
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,990
Awards: G1256221581, G6392150659, G7317512889
OpenAlex ID: W7140179959