{"doi":"10.1093/jimmun/vkaf117","title":"Therapeutic potential of NRF2 activating drug RTA-408 in suppressing T cell effector responses and inflammatory bowel disease","abstract":"RTA-408, also known as Omaveloxolone, is an FDA-approved drug for treating Friedrich's Ataxia, a neurological disorder. It is a triterpenoid compound that activates nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of cellular redox balance. In this study, we explored the impact of RTA-408 on T cells and evaluated its therapeutic potential in inflammatory bowel disease (IBD). In vitro activation of murine and human T cells in the presence of RTA-408 resulted in suppressed proliferation, reduced expression of IFN-γ, cytotoxic granules and IL-17, but enhanced frequency of Foxp3+ Treg cells. Treatment of Nrf2-deficient T cells with RTA-408 revealed that while the reduction in CD69 expression, IL-2, and IFN-γ levels is NRF2-dependent, the suppression of T cell proliferation and granzyme B/perforin expression occurs independently of NRF2. In vivo administration of RTA-408 alleviated the disease severity in DSS-induced colitis mice by decreasing colonic T cell counts and their inflammatory cytokine production. Additionally, ex vivo treatment of T cells from IBD patients with RTA-408 reduced their expansion and IL-17 expression. Transcriptomic and metabolic analyses revealed that RTA-408 reduces glycolysis and mitochondrial respiration in T cells and reprograms their metabolism towards pentose phosphate pathway and glutaminolysis. Our findings highlight the potential of RTA-408 as a modulator of T cell homeostasis, metabolism, and inflammation, supporting its repurposing for inflammatory diseases like IBD.","journal":"The Journal of Immunology","year":2025,"id":531555,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"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":1049016,"name":"Aprajita Tripathi","orcid":null,"position":1,"is_corresponding":false},{"id":1389069,"name":"Rachel Griffard","orcid":"0000-0002-3330-695X","position":2,"is_corresponding":false},{"id":1019692,"name":"Nanda Kumar Yellapu","orcid":"0000-0002-3095-6375","position":3,"is_corresponding":false},{"id":1113855,"name":"Poojaben Dhorajiya","orcid":null,"position":4,"is_corresponding":false},{"id":854603,"name":"Kalyani Pyaram","orcid":"0000-0003-2744-7470","position":5,"is_corresponding":false},{"id":1048314,"name":"Debolina Dasgupta","orcid":"0000-0002-4953-8026","position":0,"is_corresponding":true}],"reference_count":105,"raw_metadata":null,"created_at":"2026-07-19T02:51:14.579161Z","pmid":"40570091","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":[]}