Abstract

Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid neoplasms characterized by treatment difficulties and a propensity to progress to acute myeloid leukemia. Impaired natural killer (NK) cell surveillance is a hallmark of MDS, yet the underlying molecular mechanisms remain poorly understood. This study aims to elucidate the mechanism by which HIF-1α regulates NK cell differentiation disorders and its impact on NK cell cytotoxicity in MDS. Flow cytometry was employed to compare HIF-1α expression and NK cell differentiation between wild-type and NUP98/HOXD13 (NHD13) mice. Our results demonstrated a significant increase in HIF-1α expression in the bone marrow and peripheral blood of MDS mice, accompanied by a notable decrease in immature NK cell subsets and activating receptors (NKG2D, NKp44, and DNAM-1). Overexpression of HIF-1α in human NK cells or pharmacological stabilization with CoCl2 inhibits the differentiation into mature NK cells, suppresses the expression of degranulation molecules such as Granzyme B, and impairs NK cell cytotoxicity. Western blot analysis indicated that HIF-1α regulates NK cell differentiation and function via the JAK1/STAT5/SOCS2 signaling pathway. Collectively, these findings suggest that the hypoxic microenvironment in MDS enhances HIF-1α expression, which subsequently impairs NK cell maturation and inhibits their cytotoxicity. Targeting HIF-1α may delay MDS progression by enhancing NK cell function via the JAK1/STAT5/SOCS2 signaling pathway.