Inhibition of glutamine synthetase enhances hepatocellular carcinoma radiosensitivity through ROS-induced excessive mitophagy

Oct 23, 2025Molecular biology reports

Blocking glutamine synthetase may make liver cancer cells more sensitive to radiation by causing harmful mitochondrial breakdown through increased reactive oxygen species

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

A positive association between GS expression and mitophagy-related genes in hepatocellular carcinoma (HCC) was observed.

Inhibition of glutamine synthetase (GS) with L-methionine sulfoximine (MSO) increased the effects of radiotherapy in HCC cells.
MSO treatment led to elevated reactive oxygen species (ROS) production and decreased antioxidant capacity, resulting in greater mitochondrial damage.
Mitophagy was activated as indicated by the accumulation of LC3-II and upregulation of the PINK1/Parkin pathway.
The radiosensitizing effect of MSO was partially reversed by Mdivi-1, suggesting that mitophagy is involved in this process.
These findings suggest that targeting GS may improve radiotherapy outcomes by enhancing oxidative stress and mitophagy in HCC.

AI simplified

BACKGROUND: Glutamine' synthetase (GS) plays a central role in glutamine metabolism and has been implicated in the progression and treatment resistance of hepatocellular carcinoma (HCC). Although previous studies have explored GS in tumor metabolism, its role in modulating mitophagy and radiosensitivity in HCC cells remains unclear.

METHODS: We analyzed GS expression in HCC using data from the TCGA database, followed by treatment of HepG2, Hep3B and Huh7 cells with the GS inhibitor L-methionine sulfoximine (MSO) and exposure to ionizing radiation. Cellular responses were evaluated through CCK-8 assays, Western blotting, immunofluorescence, flow cytometry, colony formation assays, and mitochondrial membrane potential measurements.

RESULTS: Correlation analysis revealed a positive association between GS expression and mitophagy-related genes in HCC. MSO treatment enhanced the effects of radiotherapy, leading to increased ROS production, reduced antioxidant capacity, and aggravated mitochondrial damage. Mitophagy activation was confirmed by LC3-II accumulation and upregulation of the PINK1/Parkin pathway. Notably, the radiosensitizing effect of MSO was partially reversed by Mdivi-1, indicating that mitophagy contributes to MSO-mediated radiosensitization.

CONCLUSION: These findings indicate that inhibition of GS enzyme activity enhances oxidative stress and mitophagy, thereby promoting radiosensitivity in HCC cells. This study provides new insights into the role of GS in overcoming radiotherapy resistance and highlights its potential as a therapeutic target to improve radiotherapeutic outcomes in HCC.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text (HTML) ↗

Inhibition of glutamine synthetase enhances hepatocellular carcinoma radiosensitivity through ROS-induced excessive mitophagy

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief