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Glioblastoma is highly invasive, infiltrating surrounding brain parenchyma, and is known to cause intracranial metastasis resulting in a dismal prognosis. Hypoxia contributes significantly to chemo\u2010 and radiotherapy resistance in cancer. Ferroptosis is a nonapoptotic oxidative cell death that has been identified as a potential anticancer mechanism. Sulfasalazine (SAS) activates ferroptosis and plays a potential role in tumor treatment. However, the relationship between hypoxia and SAS resistance has not been elucidated. This study is aimed at investigating the role of hypoxia in SAS\u2010induced ferroptosis and the underlying mechanisms. Here, we found that hypoxia significantly suppressed SAS\u2010induced ferroptosis by upregulating SLC7A11 expression in the U87 and U251 glioma cell lines. Hypoxia promotes SLC7A11 expression by enhancing the PI3K\/AKT\/HIF\u20101<jats:italic>\u03b1<\/jats:italic> pathway. The AKT inhibitor MK\u20102206 and HIF\u20101<jats:italic>\u03b1<\/jats:italic> inhibitor PX\u2010478 significantly reversed this effect. In addition, under normoxia, PX\u2010478 induced a higher lipid peroxidation level by decreasing SLC7A11 expression in the U87 and U251 cells but could not induce cell death directly; it could significantly enhance the tumor cell killing effect of SAS. In vivo, the combination of PX\u2010478 and SAS had a coordinated synergistic effect on anticancer activity, as revealed by subcutaneous and orthotopic xenograft mouse models. In conclusion, hypoxia enhanced glioma resistance to SAS\u2010induced ferroptosis by upregulating SLC7A11 via activating the PI3K\/AKT\/HIF\u20101<jats:italic>\u03b1<\/jats:italic> axis. Combination therapy with PX\u2010478 and SAS may be a potential strategy against glioma.<\/jats:p>","DOI":"10.1155\/2022\/7862430","type":"journal-article","created":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T01:35:11Z","timestamp":1668821711000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Hypoxia Enhances Glioma Resistance to Sulfasalazine\u2010Induced Ferroptosis by Upregulating SLC7A11 via PI3K\/AKT\/HIF\u20101<i>\u03b1<\/i> 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