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.

Keywords: Nrf2 activating drugs; antioxidation; cytokines; immunometabolism; ulcerative colitis.