Fig. 1

Oxygen-dependent regulatory pathway of HIF-1α. (1) The oxygen-dependent regulatory pathway of HIF-1α encompasses two mechanisms: Under normal oxygen levels, the stability of HIF-1α is controlled by intracellular prolyl hydroxylase (PHD), which modifies specific proline residues on HIF-1α through hydroxylation when oxygen levels are sufficient. The VHL protein (Von Hippel–Lindau protein) is also involved in oxygen-dependent regulation, leading to the ubiquitination and subsequent degradation of HIF-1α. However, under hypoxic conditions or reduced oxygen levels, decreased PHD activity diminishes the degradation of HIF-1α, resulting in increased protein stability and the capacity to enter the nucleus and activate HIF-1α-dependent gene transcription. (2) Factor-inhibiting HIF (FIH) protein is another crucial oxygen-dependent regulatory protein. Under normoxic conditions, FIH restricts the transcriptional activity of HIF-1α by hydroxylating aspartic acid residues on HIF-1α, thereby impeding its binding to the transcriptional cofactor p300/CBP. Conversely, under hypoxic conditions, decreased activity of FIH allows HIF-1α to enhance its transcriptional activity by binding to p300/CBP. EIF4E, HIF-1α, HIF-1β, and the coactivators p300/CBP form a complex to activate downstream target genes as part of the hypoxia response. Under low oxygen conditions, HIF-1α stability is enhanced, enabling it to translocate to the cell nucleus, where it dimerizes with HIF-1β to form the HIF-1 complex. This complex binds to hypoxia response elements in the promoter regions of target genes. Concurrently, p300/CBP coactivators interact with the HIF-1 complex, enhancing its transcriptional activity. EIF4E, a key post-transcriptional regulatory factor, interacts with the HIF-1/p300/CBP complex, modulating the translation of specific mRNAs, and resulting in enhanced protein synthesis. This collective action serves to activate downstream target genes involved in the cellular response to low oxygen levels and related biological processes