Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis

Haematopoietic stem cells (HSCs) rely on precisely coordinated metabolic programs to preserve their functionality, adapt to environmental cues, and sustain lifelong haematopoiesis. Here we analyse recent advances in understanding the metabolic landscape of HSCs, emphasizing how their intrinsic bioenergetic programs facilitate quiescence, self-renewal and differentiation. We also summarize the dynamic metabolic interactions with the bone marrow microenvironment, including stromal cells, osteoblasts, endosteal cells and adipose tissue, highlighting how they support proper HSC fate. In addition, we discuss how alterations in metabolic homeostasis in healthy and aged HSCs are linked to haematological disorders, particularly leukaemogenesis. We discuss metabolic dysregulation in leukaemic cells that maintains malignant persistence by mimicking certain intrinsic–extrinsic key HSC metabolic features, while simultaneously activating distinct metabolic pathways to support their growth and survival. Understanding the complex role of metabolism in HSC biology will be essential to advance regenerative medicine and blood cancer prevention strategies.