{"doi":"10.1101/2025.04.03.645598","title":"CDDO-Imidazole regulates RBC alloimmunization to the KEL antigen by activating Nrf2","abstract":"Abstract During red blood cell (RBC) transfusion, production of alloantibodies can promote significant hemolytic events. However, most transfusion recipients do not form anti-RBC alloantibodies. Identifying mechanisms that inhibit alloimmunization may lead to prophylactic interventions. One potential regulatory mechanism is activation of the transcription factor, nuclear factor erythroid-derived 2-like 2 (Nrf2), a master regulatory of antioxidant pathways. Pharmacologic Nrf2 activators improve sequelae of sickle cell disease in pre-clinical models. The Nrf2 activator, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), suppresses production of inflammatory cytokines including type 1 interferons (IFNα/β), which have been implicated in promoting RBC alloimmunization in transfusion models. Thus, we tested the hypothesis that the Nrf2 activator, CDDO-Im, regulates RBC alloimmunization. Here, we report that CDDO-Im induced Nrf2 activated gene expression and suppressed poly(I:C)-induced IFNα/β-stimulated gene (ISG) expression in human macrophages and murine blood leukocytes. In addition, following transfusion of wildtype mice with RBCs expressing the KEL antigen, CDDO-Im treatment inhibited poly(I:C)-induced anti-KEL IgG production and promoted post-transfusion recovery of KEL+ RBCs, but failed to do so in Nrf2 -/- mice. Results indicate that activation of the Nrf2 antioxidant pathway regulates RBC alloimmunization to the KEL antigen in a pre-clinical model. If findings translate to other models and human studies, Nrf2 activators may represent a potential prophylactic intervention to inhibit alloimmunization. Key Points The antioxidant pathway, Nrf2, inhibits anti-RBC alloantibody responses in a pre-clinical transfusion model. Nrf2 activation may represent a prophylactic strategy to inhibit RBC alloimmunization in transfusion recipients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":563797,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"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":1467005,"name":"Rosario Hernandez-Armengol","orcid":null,"position":1,"is_corresponding":false},{"id":1294280,"name":"Kausik Paul","orcid":null,"position":2,"is_corresponding":false},{"id":370733,"name":"Juneyoung Lee","orcid":"0000-0001-8073-9304","position":3,"is_corresponding":false},{"id":615112,"name":"Karina Nance","orcid":"0000-0001-8668-2310","position":4,"is_corresponding":false},{"id":920666,"name":"Tomohiro Shibata","orcid":"0000-0002-8766-4250","position":5,"is_corresponding":false},{"id":907254,"name":"Peibin Yue","orcid":"0000-0001-6328-8441","position":6,"is_corresponding":false},{"id":233908,"name":"Christian Stehlik","orcid":"0000-0002-3782-2484","position":7,"is_corresponding":false},{"id":370735,"name":"David R. Gibb","orcid":"0000-0001-5863-3239","position":8,"is_corresponding":false},{"id":1036001,"name":"Che‐Yu Chang","orcid":"0000-0003-4404-9247","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:56:17.117043Z","pmid":"40235992","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":[]}