As2S2 restores erythroid maturation in sf3b1-deficient zebrafish by upregulating smad7

SF3B1 is among the most frequently mutated genes in myelodysplastic syndromes (MDS) and is closely associated with aberrant erythropoiesis, yet strategies to restore terminal erythroid maturation in SF3B1-linked disease are limited. Using a zebrafish sf3b1 knockdown model, we demonstrate that arsenic disulfide (As2S2) reinstates erythroid reporter expression and hemoglobinization in morphants and yields partial persistence of rescue at later stages. Integrated transcriptomic analyses show that As2S2 remodels metabolic and translational programs and attenuates TGF-ß pathway activity, notably inducing the inhibitory mediator smad7. Combining smad7 overexpression with pharmacologic TGF-ß inhibition enhances recovery, consistent with a Smad7-dependent mechanism. These results identify As2S2 as an in vivo chemical probe that counteracts sf3b1-dependent erythroid failure via upregulation of Smad7 and highlight Smad7 as a candidate for therapeutic modulation in SF3B1- associated ineffective erythropoiesis. Overall design: mRNA profiling by high throughput sequencing to dissect the molecular mechanism by which As2S2 rescues erythroid maturation defects via regulating Smad7/TGF-ß axis in SF3B1 knockout zebrafish model