• Excess heme drives ferroptosis in sickle erythroblasts by disrupting glutamine-glutamate metabolism resulting in glutathione depletion. • Heme-induced mitochondrial dysfunction promotes L-2-hydroxyglutarate accumulation, histone hypermethylation and glutaminase suppression. Sickle cell disease (SCD) is characterized by chronic hemolysis and excess free heme, which drives oxidative stress, inflammation, and progressive organ damage. While the pathological consequences of heme are well recognized, its direct impact on erythroid metabolism and epigenetic regulation remains incompletely understood. Here, we demonstrate that excess heme acts as a central metabolic-epigenetic disruptor in sickle erythroblasts, triggering ferroptosis through coordinated suppression of glutamine metabolism and mitochondrial function. Hemin exposure induced robust lipid peroxidation and ferroptotic cell death, accompanied by impaired cystine uptake, glutathione depletion, and increased ferroptosis markers. Mechanistically, heme selectively repressed the catalytically active glutaminase isoform GAC, leading to reduced intracellular glutamate availability and compromised redox homeostasis. At the epigenetic level, heme promoted global histone hypermethylation and chromatin compaction at genes governing glutamine and glutamate metabolism. This effect was driven by mitochondrial dysfunction and disruption of the oxoglutarate dehydrogenase complex, resulting in accumulation of L-2-hydroxyglutarate, a potent inhibitor of α-ketoglutarate-dependent histone demethylases. Stable isotope tracing confirmed enhanced glutamine flux toward 2-oxoglutarate and L-2-hydroxyglutarate under heme stress. Importantly, supplementation with the cell-permeable α-ketoglutarate analog dimethyl-α-ketoglutarate restored TCA cycle activity, reduced histone hypermethylation, rescued glutaminase expression, replenished glutathione, and alleviated heme-induced ferroptosis. Together, these findings uncover a previously unrecognized metabolic-epigenetic circuit linking excess heme to mitochondrial dysfunction, chromatin remodeling, and ferroptosis in sickle erythropoiesis, and identify metabolic repletion strategies as potential therapeutic treatment approaches for SCD.
Xi et al. (Fri,) studied this question.