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However, little is understood about the regulatory mechanism of nuclear \u03b2\u2010catenin in HPC\u2010mediated cerebral ischemic tolerance. Although lysine(K)\u2010specific demethylase 2A (KDM2A) has been known as a crucial regulator of nuclear \u03b2\u2010catenin destabilization, whether it plays an important role through modulating nuclear \u03b2\u2010catenin in cerebral ischemic tolerance induced by HPC remains unknown. In this study, we explored the molecular mechanism of stabilizing nuclear \u03b2\u2010catenin by inhibiting KDM2A\u2010mediated demethylation in the HPC\u2010offered neuroprotection against tGCI. In addition, we confirmed that nuclear methylated\u2010\u03b2\u2010catenin in CA1 decreased and nuclear \u03b2\u2010catenin turnover increased after tGCI, which were reversed by HPC. The administration with methyltransferase inhibitor AdOx abrogated HPC\u2010induced methylation and stabilization of nuclear \u03b2\u2010catenin in CA1, as well as the neuroprotection against tGCI. Notably, HPC downregulated the expression of KDM2A in CA1 and reduced the interaction between KDM2A and \u03b2\u2010catenin in the nucleus after tGCI. The knockdown of KDM2A with small\u2010interfering RNA could upregulate nuclear methylated\u2010\u03b2\u2010catenin and stabilize \u03b2\u2010catenin, thereby increasing survivin in CA1 and improving the cognitive function of rats after tGCI. Opposite results were observed by the administration of\n                    <jats:italic>KDM2A<\/jats:italic>\n                    \u2010carried adenovirus vector. Furthermore, we demonstrated that KDM2A mediates the demethylation of nuclear \u03b2\u2010catenin through jumonji C (JmjC) domain of KDM2A in HEK\u2010293T and SH\u2010SY5Y cells. Our data support that the inhibition of KDM2A\u2010mediated demethylation of nuclear \u03b2\u2010catenin contributes to HPC\u2010induced neuroprotection against tGCI.\n                  <\/jats:p>","DOI":"10.1096\/fj.202201657","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T11:29:22Z","timestamp":1675250962000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Stabilization of nuclear \u03b2\u2010catenin by inhibiting\n                    <scp>KDM2A<\/scp>\n                    mediates cerebral ischemic tolerance"],"prefix":"10.1096","volume":"37","author":[{"given":"Yunyan","family":"Zuo","sequence":"first","affiliation":[{"name":"Department of Neurology Institute of Neurosciences, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University  Guangzhou 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