{"doi":"10.1016/j.jbc.2025.110238","title":"Blockade of the estrogen receptor alpha–pregnane X receptor axis protects ovariectomized mice against ethanol-induced hepatotoxicity","abstract":"Women develop alcohol-associated liver disease (ALD) faster than men at any level of alcohol consumption, implicating estrogen as a contributing factor. However, the precise mechanism remains unknown. Therefore, 12-week-old female C57BL/6N mice were subjected to either bilateral ovariectomy (OVX) or sham surgery. After a 3-week recovery period, the mice were fed either a 5% ethanol (EtOH)-containing liquid diet or paired-fed control diet for 10 days followed by a single gavage dose of EtOH (5 g/kg, 30% EtOH solution). The mice were examined for serum biochemical parameters, hepatotoxicity, histology, expression of xenobiotic nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor, and their target gene mRNAs and proteins in hepatic and perigonadal white adipose tissues (pgWATs). While OVX mice on a control diet significantly gained weight, EtOH significantly increased hepatotoxicity, residual EtOH levels, lipid peroxidation, and oxidative stress in sham-operated mice but not in their OVX counterparts. In addition, in the livers and pgWAT of the sham mice, EtOH significantly increased the mRNA and/or protein levels of the major estrogen receptor (estrogen receptor α), PXR, constitutive androstane receptor, and their target genes, proinflammatory cytokines and chemokines, lipogenic genes, and fibroblast growth factor 21 levels, a predictive biomarker for ALD severity in humans, but inhibited nuclear factor erythroid 2-related factor 2 (NRF2) and its target genes encoding NQO1 and BHMT (betaine-homocysteine S-methyltransferase). Unexpectedly, all these changes were attenuated in the EtOH-fed OVX mice by the upregulation of NRF2 and aryl hydrocarbon receptor and their downstream antioxidant target genes. Together, these results suggest the existence of an estrogen-regulated estrogen receptor α-PXR-NRF2 signaling axis in liver and pgWAT, which contributes to sexual dimorphism in ALD.","journal":"Journal of Biological Chemistry","year":2025,"id":544215,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1221977,"name":"Malvin Ofosu‐Boateng","orcid":"0000-0002-1407-1876","position":1,"is_corresponding":false},{"id":1221980,"name":"Daniel Okwudili Nnamani","orcid":"0000-0002-6788-3835","position":2,"is_corresponding":false},{"id":1221979,"name":"Lidya H Gebreyesus","orcid":"0000-0002-5540-637X","position":3,"is_corresponding":false},{"id":1222518,"name":"Nour Yadak","orcid":null,"position":4,"is_corresponding":false},{"id":381663,"name":"Kusum K. Kharbanda","orcid":"0000-0001-7759-8889","position":5,"is_corresponding":false},{"id":281044,"name":"Frank J. Gonzalez","orcid":"0000-0002-7990-2140","position":6,"is_corresponding":false},{"id":317305,"name":"Maxwell A. Gyamfi","orcid":"0009-0005-8403-9467","position":7,"is_corresponding":false},{"id":1222517,"name":"Elizabeth Twum","orcid":null,"position":0,"is_corresponding":true}],"reference_count":99,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:53:12.864581Z","pmid":"40381698","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}