Nrf2 sensitizes ferroptosis through l-2-hydroxyglutarate–mediated chromatin modifications in sickle cell disease

Sickle cell disease (SCD) is a chronic hemolysis, constant oxidative stress, and systemic hypoxia condition, and undergoes significant metabolic alterations. However, little is known about the correlation between metabolic alterations and those pathophysiological symptoms. Here we report that Nrf2, a master regulator of cellular antioxidant responses, regulates the production of the metabolite L-2-hydroxyglutarate (L2HG) to mediate epigenetic histone hypermethylation for gene expression involved in metabolic, oxidative and ferroptosis stress responses in SCD. Mechanistically, Nrf2 was found to regulate the expression of L-2-hydroxyglutarate dehydrogenase (L2hgdh) to mediate L2HG production under hypoxia. Gene expression profile analysis indicates that reactive oxygen species (ROS) and ferroptosis response are the most significantly affected signaling pathways after Nrf2 ablation in SCD. Nrf2 silencing and L2HG supplementation sensitize human sickle erythroid cells to the ROS and ferroptosis stresses. The absence of Nrf2 and accumulation of L2HG significantly affect histone methylation for chromatin structure modification and reduce the assembly of transcription complexes on downstream target genes to regulate ROS and ferroptosis responses. Furthermore, pharmacological activation of Nrf2 was found to render protective effects against ROS and ferroptosis stresses in SCD mice. Our data suggest a novel mechanism by which Nrf2 regulates L2HG levels to mediate SCD severity through ROS and ferroptosis stress responses and targeting Nrf2 is a viable therapeutic strategy to ameliorate SCD symptoms.