Nrf2-regulated L-2-hydroxyglutarate sensitizes erythroid cells to ferroptosis in sickle cell disease

SCD had hemolysis with elevated levels of heme and iron, which induced ferroptosis. Here, we found Nrf2 knockout in SCD mice accumulated the levels of the metabolite L-2-hydroxyglutarate (L2HG), which impaired ferroptosis stress response to exacerbate SCD symptom. Mechanistically, L2HG was found to regulate the expression of genes involved in the iron and heme metabolism via histone epigenetic hypermethylation. Our findings indicate an important role of Nrf2/L2HG in SCD for ferroptosis response. Overall design: Comparison of spleen erytrhoid cells transcriptome in sickle cell disease Nrf2 WT (3 samples) and Nrf2 KO mice (3 samples) at 2-3 month of age.