Therapeutic Potential of NRF2 activating drug RTA-408 in suppressing T-cell effector responses and inflammatory bowel disease

Targeting T-cells has emerged as a promising therapeutic strategy for treating inflammatory diseases. Triterpenoids, classified as antioxidant inflammatory modulator (AIM) compounds, are known to influence immune cell functions. RTA-408 is an AIM drug that was approved last year for the treatment of neurological disorders. In this study, we demonstrate the anti-inflammatory effects of RTA-408, on both mouse and human T-cells. At picomolar concentrations, RTA-408 robustly induces NRF2 activation in T-cells and reduces T-cell activation, proliferation, and cytokine functions. In in vitro activated CD4 and CD8 T-cells isolated from mice and human blood, we observed a significant decrease in proliferation, and expression of inflammatory cytokine IFN-γ, and cytotoxic granules (perforin and granzyme B). Mechanistically, treatment with RTA-408 significantly suppressed glycolysis and mitochondrial respiration in human T-cells, while increasing the expression of pentose phosphate pathway genes, such as transketolase (TKT) and transaldolase (TALDO). These findings suggest that RTA-408 modulates T-cell metabolism. Furthermore, treatment of circulating T-cells from inflammatory bowel disease (IBD) patients with RTA-408 caused a reduction in expansion and the expression of the inflammatory cytokine IL-17. Our results highlight the therapeutic potential of RTA-408 in treating chronic inflammatory conditions like IBD by modulating T-cell activity.