Non-Canonical Heme Oxygenase-1 Function in Hematopoietic Stem Cell Homeostasis and Aging

Heme oxygenase-1 (HO-1, encoded by Hmox1) is a cytoprotective enzyme with well-established roles in defending against oxidative stress. Global Hmox1 deficiency in mice accelerates hematopoietic stem cell (HSC) exhaustion and aging, effects previously attributed primarily to loss of HO-1 activity within the bone marrow (BM) niche. However, the cell-intrinsic contribution of HO-1 to HSC regulation has remained unclear. Here, we show that global Hmox1 deficiency results in accumulation of an expanded but largely quiescent HSC pool characterized by compromised genome maintenance, altered apoptotic signaling, and defective cell-cycle checkpoint control. We further demonstrate that HO-1 protein is expressed in HSCs and exhibits a predominantly nuclear, non-canonical localization. Using Hoxb5-CreERT2-mediated conditional deletion of Hmox1 in HSCs, we uncover an intrinsic requirement for HO-1 in controlling early hematopoietic differentiation. HSC-specific loss of HO-1 skews stem cell output toward short-term progenitors and increases colony-forming capacity. Transcriptomic profiling of Hmox1fl/fl;Hoxb5-CreERT2 HSCs revealed broad dysregulation of pathways involved in translation and RNA metabolism, together with aberrant expression of key transcription factors controlling hematopoietic differentiation. Collectively, these findings identify a non-canonical, cell-intrinsic role for HO-1 in regulating HSC homeostasis, differentiation, and aging.