{"doi":"10.1016/j.redox.2025.103724","title":"Uremic toxin receptor NR1H3 contributes to hyperlipidemia- and chronic kidney disease-accelerated vascular inflammation, which is partially suppressed by novel YBX2 anti-ROS pathway","abstract":"Hyperlipidemia and chronic kidney disease (CKD) are well-established risk factors for cardiovascular disease and act synergistically to promote vascular inflammation and disease progression. However, the mechanisms underlying this synergetic effect remain largely unknown. Using a mouse model combining hyperlipidemia (via high-fat diet feeding, HFD) with 5/6 nephrectomy-induced CKD, we made the following significant findings: 1) HFD + CKD upregulated 1179 genes in mouse aortas and induced prominent reactive oxygen species (ROS), far more than either HFD or CKD alone. 2) HFD + CKD upregulated 86 CRISPRi-identified mitochondrial ROS regulators, 36 CRISPRi-identified cellular ROS regulators, and 19 GSEA-collected ROS regulators. These changes were associated with the upregulations of 48 cytokines, 7 highest toxicity uremic toxin receptors-including CD1D, FCGRT, AHR, IL6RA AGER, NR1H3 and NPY5R-in aortas. 3) These uremic toxin receptors emerged as novel promoters of inflammation and trained immunity. Deficiencies in CD1D, AHR, AGER, and the trained immunity promoter SET7 each downregulated up to 5.5 % of the genes upregulated by HFD + CKD. Conversely, activation of NR1H3 using an agonist upregulated up to 12.2 % of these genes. 4) The expression of 46 cytokine genes was strongly associated with NR1H3 upregulation. 5) The NR1H3 agonist also induced the expression of 28 ROS regulators, including YBX2, a novel anti-ROS transcription factor and RNA-binding protein, suggesting a potential negative feedback mechanism. YBX2 deficiency increased the cellular ROS level, while YBX2 overexpression suppressed 27 proinflammatory genes induced by HFD + CKD. Our findings provide novel insights into the role of the NR1H3-YBX2 axis in regulating inflammation accelerated by hyperlipidemia and CKD.","journal":"Redox Biology","year":2025,"id":519690,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"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":237312,"name":"Yu Sun","orcid":"0000-0002-0877-7186","position":1,"is_corresponding":false},{"id":239127,"name":"Fatma Saaoud","orcid":null,"position":2,"is_corresponding":false},{"id":237316,"name":"Keman Xu","orcid":"0000-0002-0816-1760","position":3,"is_corresponding":false},{"id":237315,"name":"Ying Shao","orcid":"0000-0001-5879-0154","position":4,"is_corresponding":false},{"id":1389216,"name":"Baosheng Han","orcid":null,"position":5,"is_corresponding":false},{"id":1304910,"name":"Xiaohua Jiang","orcid":"0000-0002-0823-2637","position":6,"is_corresponding":false},{"id":430274,"name":"Laisel Martinez","orcid":"0000-0002-3009-8761","position":7,"is_corresponding":false},{"id":397423,"name":"Roberto I. Vázquez-Padrón","orcid":"0000-0002-9370-276X","position":8,"is_corresponding":false},{"id":274038,"name":"Sadia Mohsin","orcid":"0000-0002-2106-1094","position":9,"is_corresponding":false},{"id":274033,"name":"Huaqing Zhao","orcid":"0000-0002-0953-4768","position":10,"is_corresponding":false},{"id":233134,"name":"Hong Wang","orcid":"0000-0001-6258-4070","position":11,"is_corresponding":false},{"id":233133,"name":"Xiaofeng Yang","orcid":"0000-0002-6854-6195","position":12,"is_corresponding":false},{"id":237313,"name":"Yifan Lu","orcid":"0000-0003-4461-0698","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:49:23.618703Z","pmid":"40505347","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":[]}