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Oxidative stress affects cell and mitochondrial membranes, altering Adp-ribosyl cyclase (CD38) and Silent message regulator 3 (SIRT3) protein expression and possibly impacting SIRT3\u2019s ability to deacetylate Tumor protein p53 (P53). This study explores the relationship between CD38, SIRT3, and P53 in H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-injured HT22 cells treated with Idebenone. Apoptosis was detected using flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining after determining appropriate H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> and Idebenone concentrations.<\/jats:p><jats:p>In this study, Idebenone was found to reduce apoptosis and decrease P53 and Caspase3 expression in H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-injured HT22 cells by detecting apoptosis-related protein expression. Through bioinformatics methods, CD38 was identified as the target of Idebenone, and it further demonstrated that Idebenone decreased the expression of CD38 and increased the level of SIRT3. An increased NAD<jats:sup>+<\/jats:sup>\/NADH ratio was detected, suggesting Idebenone induces SIRT3 expression and protects HT22 cells by decreasing apoptosis-related proteins. Knocking down SIRT3 downregulated acetylated P53 (P53Ac), indicating SIRT3\u2019s importance in P53 deacetylation.<\/jats:p><jats:p>These results supported that CD38 was used as a target of Idebenone to up-regulate SIRT3 to deacetylate activated P53, thereby protecting HT22 cells from oxidative stress injury. Thus, Idebenone is a drug that may show great potential in protecting against reactive oxygen species (ROS) induced diseases such as Parkinson\u2019s disease, and Alzheimer\u2019s disease. And it might be able to compensate for some of the defects associated with CD38-related diseases.<\/jats:p>","DOI":"10.1007\/s11064-024-04189-7","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T03:36:30Z","timestamp":1718163390000},"page":"2491-2504","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Idebenone Antagonizes P53-Mediated Neuronal Oxidative Stress Injury by Regulating CD38-SIRT3 Protein Level"],"prefix":"10.1007","volume":"49","author":[{"given":"Hao","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Jun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi-Ying","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Bo","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Yan","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Mei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,12]]},"reference":[{"issue":"9","key":"4189_CR1","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1124\/dmd.119.088047","volume":"47","author":"MI Hossain","year":"2019","unstructured":"Hossain MI, Marcus JM, Lee JH, Garcia PL, Gagn\u00e9 J-P, Poirier GG et al (2019) SULT4A1 protects against oxidative-stress Induced mitochondrial dysfunction in neuronal cells. 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