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The following is a summary of “Evaluated NSUN3 in reticulocytes from HbH-CS disease that reflects cellular stress in erythroblasts,” published in the April 2025 issue of Annals of Hematology by Liu et al. 

Hemoglobin H Disease-Constant Spring (HbH-CS) is a severe α-thalassemia variant caused by reduced α-globin synthesis. It leads to oxidative stress from excess β-globin chains and unstable Hemoglobin H (HbH) formation. 

Researchers conducted a retrospective study on HbH-CS, a severe α-thalassemia variant marked by reduced α-globin synthesis and excess β-globin aggregation. This imbalance triggered oxidative stress, elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, depleted glutathione (GSH), and activated the Nrf2- antioxidant response element (ARE) antioxidant response. 

They reported abnormal NSUN3 overexpression in reticulocytes from patients with HbH-CS and constructed an in vitro NSUN3 overexpression/silencing model using K562 cells with erythroid differentiation potential and an intact bead protein gene cluster. 

The results showed that NSUN3 overexpression significantly increased intracellular ROS and MDA levels, reduced GSH content and diminished the overall cellular antioxidant capacity (T-AOC) and inhibited the synthesis of mitochondrial respiratory chain complexes I, II, and IV through aberrant m5C→f5C modification. It also blocked Nrf2 phosphorylation, prevented its nuclear translocation, weakened the antioxidant system, increased intracellular DNA damage, and inhibited cellular proliferation, while NSUN3 silencing produced the opposite effects. 

Investigators provided initial insights into how NSUN3 modulated oxidative stress in erythrocytes through epigenetic modifications. They contributed to understanding the clinical management of patients with HbH-CS. 

Source: link.springer.com/article/10.1007/s00277-025-06359-1