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The molecular mechanisms underlying this resistance remain incompletely understood. Here, we identify karyopherin subunit alpha 3 (KPNA3) as a potential contributor to TMZ resistance. Through integrated bioinformatics analysis of TMZ\u2010resistant glioma cells (SF126R) and patient databases, we found KPNA3 expression is elevated in TMZ\u2010resistant contexts and correlates with poor prognosis in TMZ\u2010treated patients. Functional studies demonstrated that KPNA3 knockdown in resistant cells impaired malignant behaviors, re\u2010sensitized cells to TMZ\u2010induced apoptosis, and suppressed glioma stem cell (GSC) properties, including sphere formation and expression of stemness factors (OCT4, ALDH1A1). Mechanistically, KPNA3 was associated with a dual pathway: it correlated with increased expression of the DNA repair enzyme MGMT and was linked to activation of the STAT3 signaling pathway. KPNA3 knockdown reduced both MGMT levels and STAT3 phosphorylation (Tyr705). Furthermore, pharmacological inhibition of STAT3 mirrored the effect of KPNA3 knockdown by potently inhibiting GSC generation. Clinically, KPNA3 and\n                    <jats:italic>p<\/jats:italic>\n                    \u2010STAT3 protein levels were positively correlated in high\u2010grade glioma tissues. Collectively, our findings suggest that KPNA3 may play a role in concurrently enhances DNA repair and sustains the GSC population to foster TMZ resistance, identifying it as a candidate for further investigation for overcoming chemoresistance in GBM.\n                  <\/jats:p>","DOI":"10.1002\/cbin.70175","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T16:46:00Z","timestamp":1781541960000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Karyopherin Subunit Alpha 3 Drives Temozolomide Resistance in Glioblastoma by Upregulating MGMT and Activating STAT3 to Sustain Glioma Stem Cells"],"prefix":"10.1002","volume":"50","author":[{"given":"Yanru","family":"Gao","sequence":"first","affiliation":[{"name":"School of Basic Medicine Anhui Medical University Hefei Anhui China"},{"name":"Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of 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