Pharmacological targeting of xCT/system Xc- to modulate temozolomide sensitivity in glioma and glioblastoma preclinical models: a focused systematic review.

Abstract

Background: Resistance to temozolomide (TMZ) remains a major barrier in glioblastoma treatment. The cystine/glutamate antiporter system Xc-, mainly through its xCT/SLC7A11 light-chain subunit, supports cystine uptake, glutathione synthesis and redox balance, making it a biologically plausible target for modifying TMZ response. This focused systematic review evaluated whether pharmacological xCT/system Xc--relevant inhibition enhances TMZ sensitivity in glioma/glioblastoma preclinical models.

Methods: Searches were conducted in Web of Science, PubMed/MEDLINE and the Cochrane Library, with supplementary Google Scholar screening, and were completed on 30 April 2026. Reference lists of the included preclinical studies were also screened as a supplementary citation-chasing method. No lower publication-date restriction was applied. Eligible studies were primary preclinical studies using glioma/glioblastoma models, TMZ treatment, and TMZ combined with a pharmacological xCT/system Xc--relevant inhibitor or related intervention. Because the included studies differed in models, inhibitors, formulations, treatment conditions and outcome measures, findings were synthesised narratively.

Results: Ten non-retracted preclinical studies were included. Free-drug Sulfasalazine/SSZ and erastin studies provided the most directly relevant pharmacological evidence, but their effects differed by cell model, concentration, treatment duration and outcome assay. Genetic SLC7A11 manipulation supported a relationship between xCT expression, redox regulation and TMZ response, but was not treated as equivalent to pharmacological inhibition. Recent TMZ/SSZ and TMZ/erastin delivery-platform studies produced antitumour effects in TMZ-resistant and orthotopic models; however, these findings also reflected altered circulation, BBB or tumour delivery, targeting and sustained release. Sorafenib/TMZ results were inconsistent and generally lacked direct xCT/SLC7A11 assessment.

Conclusions: xCT/system Xc- targeting is a promising but preliminary preclinical strategy for modifying TMZ response. Evidence remains heterogeneous, model- and formulation-dependent, and insufficient to support clinical efficacy claims. Genetic SLC7A11 studies provide mechanistic support, while selected free-drug SSZ and erastin experiments provide limited pharmacological evidence; recent in-vivo findings are predominantly formulation-specific, and sorafenib evidence remains mixed and non-specific. Further target-engagement, pharmacokinetic, BBB, toxicity and orthotopic validation is required.