Metabolic and epigenetic interplay in HSPC specification: A balance between extrinsic and intrinsic cues

Hematopoietic stem and progenitor cells (HSPCs), including multipotent progenitors (MPPs), sustain lifelong blood production by integrating intrinsic metabolic and epigenetic mechanisms with extrinsic cues from the bone marrow (BM) niche. Epigenetic mechanisms interact with metabolic pathways to establish a coordinated network that supports HSPC maintenance and differentiation. Spatially defined signals within BM niches shape HSPC metabolic and epigenetic states and govern lineage specification. Herein, we review recent advances on the bidirectional relationship between metabolism and epigenetics in HSPCs, emphasizing how both intrinsic and niche-derived factors regulate fate decisions under steady-state and pathological conditions. Particular attention is given to the CXCL12/CXCR4 signaling axis, a central regulator of HSPC retention, migration, and quiescence, and its emerging role in orchestrating metabolic and epigenetic mechanisms. Integrating intrinsic regulatory networks with dynamic extrinsic signals provide a conceptual framework for understanding HSPC fate and may uncover strategies for regenerative medicine and hematological disease therapy.