Systemic iron restriction by vamifeport, but not dietary iron restriction, reduced hemolysis and inflammation in HbSS mice. Treatment with vamifeport, but not dietary iron restriction (LID), increased the proportion of circulating hypochromic and microcytic RBCs and reduced CHCM (A) and decreased indirect bilirubin in plasma (B), compared with HbSS mice treated with vehicle. Vamifeport, but not LID, prevented the release of sVCAM-1 into the circulation of HbSS mice (C) and reduced plasma concentrations of RANTES (D). (E) Circulating leukocyte, neutrophil, and lymphocyte numbers were normalized in HbSS mice receiving vamifeport but remained elevated in HbSS mice on LID. (F) Vamifeport, but not LID, decreased serum iron levels. LID, but not vamifeport, efficiently depleted iron from the liver (G), whereas both treatments decreased the expression of liver Hamp (H). Results are presented as individual values with mean ± standard deviation (n = 10-12 mice per group). Analysis was performed by using one-way analysis of variance with Dunnett’s multiple comparison of all groups vs the HbSS vehicle group: *P < .05, **P < .01, ***P < .001. BID, twice daily; QD, once daily.