{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:51:31Z","timestamp":1791568291413,"version":"4.3.4"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Chemother Pharmacol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Resistance to temozolomide (TMZ) remains a major barrier in glioblastoma treatment. The cystine\/glutamate antiporter system Xc\u2212, 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\u2212-relevant inhibition enhances TMZ sensitivity in glioma\/glioblastoma preclinical models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2212-relevant inhibitor or related intervention. Because the included studies differed in models, inhibitors, formulations, treatment conditions and outcome measures, findings were synthesised narratively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>xCT\/system Xc\u2212 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00280-026-04957-y","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:53:10Z","timestamp":1791521590000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological targeting of xCT\/system Xc\u2212 to modulate temozolomide sensitivity in glioma and glioblastoma preclinical models: a focused systematic review"],"prefix":"10.1007","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8982-2315","authenticated-orcid":false,"given":"Sufyan","family":"Elhashani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Elkawafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdalmanam","family":"El Shekhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanad","family":"Elrishe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud A.","family":"Aloriby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"4957_CR1","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1188\/16.CJON.S1.2-8","volume":"20","author":"ME Davis","year":"2016","unstructured":"Davis ME (2016) Glioblastoma: overview of disease and treatment. 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