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These factors induce fetal exposure to excessive maternal glucocorticoids (GCs), however, the mechanisms by which intrauterine GCs exposure programs offspring CYP expression remain unclear. Given that GCs are high\u2010affinity ligands for the glucocorticoid receptor (GR), this work employs dexamethasone (DEX), a GR agonist, to establish a prenatal dexamethasone exposure (PDE) model for investigating the role of GR activation in CYPs programming. The model is implemented to pregnant Wistar rats and heterozygous liver\u2010specific GR knockout mice. Results show that PDE consistently increases the expression of hepatic CYP3A1 and CYP2B1, thereby enhancing the metabolic enzyme efficiency in adult male offspring. In vitro experiment further validates that GC\u2010induced activation of GR increases the binding of P300\/cAMP response element\u2010binding protein (CBP) to the promoter region of constitutive androstane receptor (CAR), which leads to sustained H3K9 and H3K27 acetylation at the CAR locus, indirectly promoting CYP expression in adult offspring. Conclusively, the GR\u2010CAR pathway may play a pivotal role in programming CYP3A alteration in offspring exposed to elevated intrauterine GCs. This study provides novel insights into individual variations of CYPs expression and metabolic patterns.<\/jats:p>","DOI":"10.1002\/advs.202515583","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T04:30:02Z","timestamp":1763353802000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Pivotal Role of GR\u2010CAR Pathway in Fetal Programming of Hepatic Cytochrome P450 3A Alteration in Adulthood"],"prefix":"10.1002","volume":"13","author":[{"given":"Xiaoxiang","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Sciences Wuhan University  Wuhan 430071 China"},{"name":"Hubei Provincial Key Laboratory of Developmentally Originated Disease  Wuhan 430071 China"},{"name":"Department of Pharmacy Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medicine Jingchu University of Technology  Jingmen 448000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Sciences Wuhan University  Wuhan 430071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Sciences Wuhan University  Wuhan 430071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuerong","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Sciences Wuhan University  Wuhan 430071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Sciences Wuhan University  Wuhan 430071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics School of Basic Medical Sciences Wuhan University  Wuhan 430071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Kou","sequence":"additional","affiliation":[{"name":"Hubei Provincial Key Laboratory of Developmentally Originated Disease  Wuhan 430071 China"},{"name":"Department of Pharmacy Zhongnan Hospital of Wuhan University  Wuhan 430071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Sciences Wuhan University  Wuhan 430071 China"},{"name":"Hubei Provincial Key Laboratory of Developmentally Originated Disease  Wuhan 430071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3782-1166","authenticated-orcid":false,"given":"Yu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Sciences Wuhan University  Wuhan 430071 China"},{"name":"Hubei Provincial Key Laboratory of Developmentally Originated Disease  Wuhan 430071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,16]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2023.114011"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mie.2023.08.002"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-269043"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13232"},{"key":"e_1_2_10_5_1","first-page":"2057","volume":"19","author":"Elfaki I.","year":"2018","journal-title":"Asian Pac. 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