Fig. 1

Comparing the mechanisms of action of standard of care (S.O.C) glucocorticoids (i.e., prednisone and deflazacort) with novel dissociative steroid vamorolone and fumaric acid esters (FAE). a Glucocorticoids like prednisone (PRED), diffuse through the cell membrane, bind to the cytoplasmic nuclear hormone receptor (glucocorticoid receptor (GR)) to form a receptor-ligand complex, which translocates to the nucleus. This complex indirectly binds to the glucocorticoid response element (GRE), activating target genes that are associated with broad spectrum anti-inflammation (trans-activation), as well as the nuclear factor kappa B (NF-κB) binding element to supress transcription of master inflammatory regulator, NF-κB (trans-repression). These mechanisms elicit the beneficial effects of glucocorticoids in DMD. In contrast, adverse effects are mediated through direct binding of the GR-ligand complex to negative GRE on other target genes, which represses their transcription (cis-repression). b Similarly, vamorolone binds to the GR and retains the anti-inflammatory effects characteristic of standard of care glucocorticoids, inducing transrepression with hardly any transactivation or cis-repression to elicit fewer adverse effects. c Therapeutic efficacy of FAEs is mediated through the dual activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional pathway and hydroxycarboxylic acid receptor 2 (HCAR2). Nrf2 regulates the essential cellular defence system when electrophiles/FAE bind and disrupt the interaction between Nrf2 and its negative repressor (Kelch-like ECH-associated protein 1 (Keap1)). This disruption allows Nrf2 to translocate to the nucleus, bind to the antioxidant response element (ARE) resulting in cytoprotection. Nrf2 and HCAR2 both strongly inhibit NF-κB signalling within the cellular inflammatory response. Created with BioRender.com