Mechanistically, the metabolically driven differentiation is independent of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine 5′-monophosphate–activated protein kinase (AMPK) and is instead mediated by protein kinase C. Our findings suggest that folate deprivation–induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate deficiency–induced anemia. Here, PRKAA1 is linked to folate deficiency.