MK-6482 reversed polycythemia in VhlR200W, Irp1-KO, and double-mutant VhlR200W;Irp1-KO mice. Hematocrit levels, as determined by the capillary centrifugation method (A-B), hemoglobin (C), RBC (D), MCV (E), and MCH (F) levels of 6- to 11-month-old WT, VhlR200W, Irp1-KO, and double-mutant VhlR200W;Irp1-KO mice treated with vehicle or the Hif-2α inhibitor MK-6482. Oral administration of MK-6482 significantly decreased the elevated hematocrit, hemoglobin, and RBC levels, and ameliorated polycythemia in all 3 mutant models. MK-6482 also decreased MCV and MCH values in the mutant mice. Notably, MCV and MCH levels were decreased in the Irp1-KO mice, suggesting that IRP1 deficiency induces mild iron deficiency that is reversed by VhlR200W mutation. ***P < .001, by ordinary 1-way ANOVA (multiple comparisons). D-mutant, double-mutant VhlR200W;Irp1-KO mouse.