ABSTRACT Sickle cell disease (SCD) and ?-thalassemia are genetic disorders affecting the structure or production of hemoglobin. They are growing global health burden afflicting millions around the world. Sufficient fetal hemoglobin (HbF) induction can reduce morbidity and mortality in SCD. The same is true for β-thalassemia. The standard current therapy for HbF induction in SCD hydroxyurea (HU) which in adults, does not usually ameliorate sufficiently either sickle vaso-occlusion or hemolysis. Therefore, the search for more effective and safer small molecule HbF inducers is a key unmet need in the management of SCD. We recently discovered that the peroxisome proliferator activated receptor gamma coactivator-1 (PGC-1α) is involved in the regulation of the globin genes. Upregulation of PGC-1α by lentivirus infection or by a small molecule compound ZLN005 in human primary erythroid progenitor CD34+ cells induced HbF expression and increased the percent of F-cells without affecting cell proliferation and differentiation. Activation of PGC-1α by ZLN005 might provide a new path into hemoglobin regulation with a promising therapeutic benefit in SCD. We intend to test for in vivo therapeutic effects of ZLN005 in sickle cell mice. The findings from these preclinical studies could provide initial proof of principle for developing safer, more beneficial small molecule therapeutics for SCD treatment and lead to early- phase clinical trials.