CHAC1-linked NRF2 protein expression participates in pancreatic islet protection by dextrorphan

The N-methyl-D-aspartate (NMDA) receptor antagonist dextrorphan (DXO) protects pancreatic islets from cell death induced by streptozotocin (STZ), inflammatory cytokines, reactive oxygen species (ROS), as well as in multiple mouse models of diabetes. Here we show that cytoprotective concentrations of DXO upregulate the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), driving the expression of its downstream target genes. Paradoxically, DXO also increases the expression of the pro-apoptotic factor CHAC1 (chaC glutathione-specific γ-glutamylcyclotransferase 1). To investigate its role, we silenced Chac1 in islets, which significantly enhanced DXO-mediated cell protection. In contrast, both pharmacological inhibition and genetic knockdown of N fe2l2 diminished the protective effects of DXO, confirming the cytoprotective role of NRF2. Conversely, pharmacological activation of NRF2 did not further enhance DXO-induced protection. Together, our data indicate that while DXO-mediated islet protection requires induction of NRF2, its full therapeutic efficacy is limited by the simultaneous upregulation of CHAC1.