AbstractHypoxia‐inducible factor (HIF)‐1 is the key transcriptional activator mediating both adaptive and pathological responses to hypoxia. The purpose of this study was to find the role of HIF‐1 in regulating neprilysin (NEP) at the early stage of hypoxia and explore the underlying mechanism. In this study, we demonstrated that both NEP mRNA and protein levels in neuroblastoma cells were elevated in early stages of hypoxia. Over‐expression of HIF‐1α gene increased NEP mRNA/protein levels, as well as enzyme activity while knockdown of HIF‐1α decreased them. Meanwhile, HIF‐1α was shown to bind to histone deacetylase (HDAC)‐1 and reduced the association of HDAC‐1 with NEP promoter, thus activating NEP gene transcription in a de‐repression way. In summary, our results indicated that hypoxia in the early stages would up‐regulate NEP expression, in which interaction of HIF‐1α and HDAC‐1 may play a role. This study suggested that NEP up‐regulation might be an adaptive response to hypoxia, which was mediated by HIF‐1α binding to HDAC‐1 at the early stage of hypoxia. image HIF‐1 binded to and disassociated HDAC‐1 from NEP promoter, activating NEP gene expression at early stage of hypoxia. HDAC‐1 protein level was elevated at late stage of hypoxia that exceeded the binding capacity of HIF‐1 to prevent association of HDAC‐1 from NEP promoter, leading to suppression of NEP.