The role of GSK3/PPAR-δ/FAO/mitophagy pathway in regulating hematopoietic stem cell homeostasis and function Abstract Hematopoietic stem cells (HSCs) possess the abilities to both produce stem cells, a property known as self-renewal, and give rise to all differentiated hematopoietic lineages. Clinically, HSCs are therapeutically valuable for transplantation in treatment of various hematologic malignances. Despite remarkable progress made in the research of HSCs during the past three decades, the molecular mechanisms regulating HSC homeostasis and function are still not fully understood. Our previous published showed that GSK3 plays an essential role in regulating HSC homeostasis. Specifically, knockdown of Gsk3 promote transient expansion and long-term exhaustion of HSC in vivo. Our new preliminary studies demonstrated that GSK3 functions through PPAR-δ/FAO/mitophagy pathway to regulate HSC division symmetry; inhibition of GSK3 induces mitophagy and conversely, blocking PPAR-δ/FAO/mitophagy can reverse the enhanced self-renewal phenotype that is associated with GSK3 inhibition. In this study, we will first examine how GSK3 regulates PPAR-δ, which in turn regulates mitophagy and HSC division symmetry. Secondly, we will investigate whether loss-of- function of Ppar-δ, Park2 or Pink1 (two mitophagy key regulators) reverse the functional defect of Gsk3b-deficient HSC in vivo. Lastly, we will explore whether GSK3 controls FAO and lipid metabolism to regulate HSC function and homeostasis. Our study will provide significant new insights into the molecular mechanisms underlying GSK3-dependent regulation of HSC homeostasis and function. The knowledge learned may facilitate bone marrow transplantation for treating diverse hematological diseases.