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Oxidative stress, driven by disrupted redox balance and excessive reactive oxygen species (ROS), is believed to be a key pathogenic driver. This study aimed to explore the role and mechanism of the selective enhancer of Zeste homolog 2 (EZH2) methyltransferase inhibitor GSK126 in alleviating AD-related OS in AD models. Using A\u03b21-42-induced AD model rats, we conducted Morris water maze tests, histologic and immunohistochemical staining, CCK-8\/Annexin V-PI assays, Western blot, quantitative Reverse Transcription PCR (qRT-PCR), and Chromatin Immunoprecipitation quantitative Real-Time PCR (ChIP-qPCR). GSK126 shortened escape latency, reduced hippocampal pathology\/apoptosis, upregulated Superoxide dismutase 1 (SOD1), and lowered ROS\/malondialdehyde\/protein carbonyls, thereby increasing antioxidant capacity in the AD model rats. In okadaic acid-treated SH-SY5Y cells, GSK126 enhanced viability, reduced apoptosis by downregulating Bax\/c-Cas3 and upregulating Bcl-2 and upregulated SOD1 by inhibiting EZH2-mediated H3 lysine 27 trimethylation (H3K27me3) enrichment at the SOD1 promoter. SOD1 overexpression antagonized EZH2-induced damage. These results suggest that GSK126 could alleviate AD-related pathologic alterations in these models via the EZH2\u2013H3K27me3\u2013SOD1 axis, thereby suggesting a potential therapeutic target for AD.<\/jats:p>","DOI":"10.1093\/jnen\/nlag008","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:37:37Z","timestamp":1769603857000},"page":"464-474","source":"Crossref","is-referenced-by-count":1,"title":["GSK126 mitigates oxidative stress in Alzheimer disease models via an enhancer of Zeste homolog 2\u2013H3 lysine 27 trimethylation\u2013superoxide dismutase 1 axis"],"prefix":"10.1093","volume":"85","author":[{"given":"Yonghui","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Weinan Central Hospital , Weinan,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanying","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Xi\u2019an Jiaotong University , Xi\u2019an,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongliang","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Surgery (II), Xi\u2019an International Medical Center Hospital , Xi\u2019an,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"2026042915364785500_nlag008-B1","doi-asserted-by":"crossref","first-page":"S521","DOI":"10.3233\/JAD-240719","article-title":"The therapeutic potential of yoga for Alzheimer\u2019s disease: a critical review","volume":"101","author":"Brown","year":"2024","journal-title":"J Alzheimers Dis."},{"key":"2026042915364785500_nlag008-B2","doi-asserted-by":"crossref","first-page":"3800","DOI":"10.1021\/acschemneuro.4c00339","article-title":"Alzheimer\u2019s disease: exploring the landscape of cognitive 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