{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T14:49:31Z","timestamp":1777560571470,"version":"3.51.4"},"reference-count":52,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:00:00Z","timestamp":1739750400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["iubmb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech and App Biochem"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Gliomas are one of the most prevalent types of solid tumors in the brain. Imbalances in mitochondrial metabolism have been implicated in the pathological progression of gliomas. Etomidate, an agonist of the \u03b3\u2010aminobutyric acid type A (GABAA) receptor, is widely used in clinical settings. In this study, we report a novel pharmacological function of etomidate in regulating mitochondrial metabolism in glioma cancer cells. U87 glioma tumor cells were treated with etomidate (0.5, 1.0, and 2.0\u00a0\u00b5g\/mL) for 24\u00a0h. Quantitative real\u2010time PCR, western blot analysis, mtDNA\/nDNA ratio, MitoTracker Red staining, Complex I and IV activity, intracellular ATP levels, and mitochondrial respiration were assessed. First, etomidate exposure inhibited the expression of PGC\u20101\u03b1 in U87 glioma tumor cells. Further investigation revealed that etomidate suppressed the expression of Nrf1 and TFAM, the two key executors of mitochondrial biogenesis. Etomidate treatment led to damage in mitochondrial biogenesis by decreasing the mtDNA\/nDNA ratio, reducing the protein expression of cytochrome B, and lowering mitochondrial mass. These changes suggest impaired mitochondrial replication and function. Correspondingly, etomidate exposure induced a \u201closs of mitochondrial function\u201d by diminishing the activities of Complex I and Complex IV, the mitochondrial respiratory rate (MRR), and ATP generation. These effects highlight the detrimental impact of etomidate on the energy metabolism of glioma cells. Mechanistically, etomidate inactivated the transcription factor CREB by reducing its phosphorylation at Ser133. Activation of CREB with the second messenger cAMP restored the expression of PGC\u20101\u03b1, the mtDNA\/nDNA ratio, Complex IV activity, summarized mitochondrial respiratory rate (MRR), and ATP production. This suggests that CREB activation may serve as a potential therapeutic strategy to counteract etomidate's inhibitory effects on mitochondrial function in glioma cells. Our results suggest that damage to mitochondrial biogenesis is a key step in the anticancer properties of etomidate in gliomas, and the decrease in PGC\u20101\u03b1 and its downstream molecules may be the critical mechanism behind this effect.<\/jats:p>","DOI":"10.1002\/bab.2722","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T03:19:47Z","timestamp":1739762387000},"page":"1139-1147","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Etomidate Induces Mitochondrial Dysfunction in Glioma Cancer Cells by Inhibiting Mitochondrial Biogenesis Mediated by CREB\/PGC\u20101\u03b1"],"prefix":"10.1002","volume":"72","author":[{"given":"Hailiang","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Neurosurgery The First People's Hospital of Jiangxia District, Wuhan City Wuhan Hubei China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhongcheng","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Ezhou Central Hospital Ezhou Hubei China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2035-9627","authenticated-orcid":false,"given":"Kai","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Hubei Maternal and Child Health Hospital Wuhan Hubei China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,2,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0014-3"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/adbi.201900312"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2017.0166"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noy131"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12432"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222111338"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15194"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-023-00975-7"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1139\/apnm-2020-0005"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-0889"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2016.09.006"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2011.07.008"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00292.2010"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010\u2010023\u201004892\u2010z"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.1.53"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20160622"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2014.10.062"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-021-01038-6"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.05.051"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/aas.12289"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10863-006-9013-6"},{"issue":"3","key":"e_1_2_8_23_1","first-page":"3137","article-title":"Anesthetic Agent Etiomidate Induces Apoptosis in N2a Brain Tumor Cell Line","volume":"18","author":"Chen H. 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