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Understanding this endogenous mechanism would reveal novel and effective neuroprotective targets for ischemic brain injury. Our previous study has implied that telomerase reverse transcriptase (TERT) is associated with IPC\u2010induced tolerance. Here, we investigated the mechanism of TERT\u2010mediated ischemic tolerance. Preconditioning was modeled by oxygen\u2010glucose deprivation (OGD) and by TERT inhibitor BIBR1532 in primary neurons. We found that ischemic tolerance was conferred by BIBR1532 preconditioning. We used the Cleavage\u2010Under\u2010Targets\u2010And\u2010Tagmentation approach, a recently developed method with superior signal\u2010to\u2010noise ratio, to comprehensively map the genomic binding sites of TERT in primary neurons, and showed that more than 50% of TERT\u2010binding sites were located at the promoter regions. Mechanistically, we demonstrated that under normal conditions TERT physically bound to many previously unknown genomic loci in neurons, whereas BIBR1532 preconditioning significantly altered TERT\u2013chromatin\u2010binding profile. Intriguingly, we found that BIBR1532\u2010preconditioned neurons showed significant up\u2010regulation of promoter binding of TERT to the mitochondrial anti\u2010oxidant genes, which were correlated with their elevated expression. Functional analysis further indicated that BIBR1532\u2010preconditioning significantly reduced ROS levels and enhanced tolerance to severe ischemia\u2010induced mitochondrial oxidative stress in neurons in a TERT\u2010dependent manner. Together, these results demonstrate that BIBR1532 confers neuronal ischemic tolerance through TERT\u2010mediated transcriptional reprogramming for up\u2010regulation of mitochondrial anti\u2010oxidation gene expression, suggesting the translational potential of BIBR1532 as a therapeutic agent for the treatment of cerebral ischemic injury and oxidative stress\u2010induced neurological disorders.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15515-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15515","type":"journal-article","created":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T08:24:31Z","timestamp":1631867071000},"page":"690-709","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pharmacological preconditioning by TERT inhibitor BIBR1532 confers neuronal ischemic tolerance through TERT\u2010mediated transcriptional reprogramming"],"prefix":"10.1111","volume":"159","author":[{"given":"Xuemin","family":"Xie","sequence":"first","affiliation":[{"name":"Clinical Neuroscience Institute The First Affiliated Hospital of Jinan University  Guangzhou China"},{"name":"Department of Neurology The First Clinical Medical School of Jinan University  Guangzhou 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Hong Kong Special Administrative Region  Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0133-1544","authenticated-orcid":false,"given":"Chi Kwan","family":"Tsang","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Institute The First Affiliated Hospital of Jinan University  Guangzhou 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