In contrast to normal erythrocytes, we revealed that genetic deletion of Sphk1 in SCD has potent anti-sickling and anti-hemolysis effects by correcting pathogenic metabolic reprogramming, channeling glucose to pentose phosphosphate pathway (PPP) relative to glycolysis, lowering 2,3-BPG production and boosting NADPH/glutathione-mediated detoxification. Here, SPHK1 is linked to Schnyder corneal dystrophy.