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Targeting GSTZ1 sensitizes KRASG12C-mutant lung cancer cells by overcoming glutathione and glycolysis pathway rewiring

ABSTRACT:

KRAS mutations are prevalent in lung cancer, but KRAS G12C inhibitors exhibit limited efficacy, partly due to metabolic adaptations, such as enhanced glutathione metabolism and increased glycolysis. Glutathione S-Transferase Zeta 1 (GSTZ1) is a metabolic enzyme that regulates cell metabolism. However, its role in KRAS-driven lung cancer remains underexplored. We recently reported that targeting GSTZ1 significantly enhances the efficacy of FDA-approved KRAS G12C inhibitors in non-small cell lung cancer cells. Untargeted metabolomics now revealed significant alterations in glutathione and glycolytic pathways, marked by lowered lactate levels and increased oxidized glutathione following GSTZ1 ablation. Moreover, pharmacological inhibition of glutathione synthesis and glucose uptake mimicked the sensitizing effects of GSTZ1 targeting. These metabolic shifts were accompanied by increased AMPK phosphorylation and reduced AKT phosphorylation, two key mediators of the response to KRAS G12C inhibition. Our findings establish GSTZ1-induced metabolic and signaling alterations as a novel mechanism of sensitization, positioning GSTZ1 as a potential therapeutic target.

INSTRUMENT(S): Liquid Chromatography MS - positive - HILIC, Liquid Chromatography MS - negative - HILIC

PROVIDER: MTBLS12791 | MetaboLights | 2026-05-15

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12791_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS12791_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12791_LC-MS_negative_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS12791_LC-MS_positive_hilic_metabolite_profiling_v2_maf.tsv	Tabular

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