{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T09:08:23Z","timestamp":1789549703483,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with temozolomide (TMZ) resistance being a major barrier to improved clinical outcomes. Dysregulated autophagy is closely associated with TMZ resistance in GBM, but the role of sodium\/hydrogen exchanger 1 (NHE1)\u2014a key regulator of intracellular pH homeostasis\u2014in this process remains uncharacterized. We established a TMZ\u2010resistant GBM cell line (U251TR) and observed that U251TR cells displayed higher autophagic activity, increased reactive oxygen species (ROS) levels, and reduced apoptotic rates compared to parental U251 cells. Treatment with the NHE1\u2010specific inhibitor HOE\u2010642 dose\u2010dependently suppressed cell viability, inhibited NHE1 activity, reduced intracellular ROS production, and promoted apoptosis in U251TR cells, with a positive feedback loop identified between NHE1 and ROS. Mechanistically, HOE\u2010642 blocked autophagic initiation and flux primarily via the ROS\u2010AKT\/ERK signaling axis, in which reduced ROS downregulated p\u2010AKT and p\u2010ERK1\/2, where ERK exerted pro\u2010autophagic effects and AKT exerted anti\u2010autophagic effects. In vivo, combined HOE\u2010642 and TMZ treatment significantly reduced xenograft tumor volume and weight, inhibited autophagy, and activated apoptosis compared to TMZ monotherapy, without causing evident systemic toxicity. Our findings identify a novel NHE1\u2010ROS\u2010AKT\/ERK\u2010autophagy regulatory axis in TMZ\u2010resistant GBM, validating NHE1 as a potential therapeutic target to enhance TMZ sensitivity by disrupting the autophagy\u2010apoptosis balance, and providing a new strategy for GBM treatment.<\/jats:p>","DOI":"10.1002\/jbt.71110","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T06:24:43Z","timestamp":1789453483000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of NHE1 Overcomes Temozolomide\u2010Resistance in Glioblastoma via ROS\u2010AKT\/ERK Axis\u2010Mediated Autophagy Suppression"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5262-382X","authenticated-orcid":false,"given":"Dan","family":"Li","sequence":"first","affiliation":[{"name":"Hebei Key Laboratory of Molecular Oncology Tangshan People's Hospital  Hebei 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