USP7 sustains hematopoietic stem cell homeostasis partially via PU.1 stabilization

Hematopoietic stem cell (HSC) self-renewal and lineage commitment are tightly controlled by post-translational mechanisms, but the contribution of deubiquitination to these processes remains unclear. Here, we define ubiquitin-specific protease 7 (USP7) as a critical regulator of HSC maintenance and hematopoietic homeostasis. Conditional Usp7 deletion in murine HSCs triggered rapid stem cell depletion, multilineage cytopenias, and systemic hematopoietic failure. Usp7-deficient HSCs displayed defective quiescence, reduced competitive repopulation capacity, and aberrant lineage differentiation. Mechanistically, USP7 directly binds and deubiquitinates the transcription factor PU.1, shielding it from proteasomal degradation. Loss of USP7 destabilized PU.1, leading to suppressed expression of PU.1 target genes critical for HSC quiescence and lineage specification. In competitive transplants, USP7-null HSCs exhibited severely impaired self-renewal, marked by diminished engraftment and differentiation. Ectopic PU.1 expression partially restored HSC function, confirming the USP7-PU.1 axis as essential for HSC integrity. Our study identifies USP7 as a post-translational checkpoint in hematopoiesis and reveals a novel deubiquitination-dependent mechanism controlling stem cell fate. These findings highlight the USP7-PU.1 interaction as a potential therapeutic target for hematopoietic disorders.