Several strategies have been explored to deplete GSH levels in cancer cells, including:

1. Inhibiting GSH synthesis by targeting enzymes like glutamylcysteine synthetase, glutathione synthetase, or γ-glutamyl transpeptidase.
2. Modulating the availability of GSH precursor amino acids like cysteine.
3. Using GSH-depleting agents like buthionine sulfoximine (BSO) or diethylmaleate (DEM).
4. Developing nanomedicines that co-deliver GSH-depleting agents along with therapeutic drugs for synergistic effects.

Depleting GSH not only enhances the cytotoxicity of chemotherapeutics, but also overcomes multidrug resistance in cancer cells. However, GSH depletion alone is often insufficient, and combination approaches with other therapies are more effective.

Overall, targeting GSH metabolism in cancer cells is a promising strategy to improve the efficacy of various cancer therapies and overcome treatment resistance, but careful modulation is required to balance its protective and pathogenic roles.

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