Fig. 3

Regulatory mechanism of HIF-1 under normoxia. HIF-1α protein is synthesized through transcription and subsequent translation. Under normal oxygen levels, the newly synthesized HIF-1α protein is hydroxylated by prolyl hydroxylase 2 (PHD2) in the presence of co-activators αKG and Fe²⁺. The dihydroxylated HIF-1α is then ubiquitinated by the von Hippel–Lindau (pVHL) and degraded by 26S proteasome. However, HIF-1α protein can remain stable in pseudohypoxia. The regulatory mechanisms are outlined as follows: A Transcriptional and translational regulation of HIF-1α: (i) Activation of the PI3K-AKT-mTOR and MAPK signaling pathways enhance the activity of transcription factors (TFs) such as: FoxK1, NF-κB, SP1, and c-MYC, leading to increased transcription of HIF-1α; (ii) Activated PI3K-AKT-mTOR and MAPK signaling pathways also facilitate the translation of HIF-1α. B Stability of HIF-1α protein by modulating its PHD status: (i) Regulation of the transcription and translation of PHD2; (ii) Metabolites and associated enzymes related to αKG; (iii) Chemical compounds or environmental factors associated with Fe²⁺. C Ubiquitination of HIF-1α: (i) Modification by SUMO1 as ub-like modifier; (ii) Deubiquitination functions of TRIM44, USP8, USP10, USP14, and USP20; (iii) Disruption of pVHL-HIF-1α binding by proteins such as PARK7/DJ-1 and lncRNA MALAT1; (iv) A decrease in pVHL concentration induced by glucocorticoid and radiation treatment. D Transcriptional activation regulation of HIF-1α. Heat shock proteins HSP90, HSP60, HSP70, and MUC1 are shown to promote the stability of HIF-1α, while SIRT1, FIH1, and EAF2 are shown to reduce its stability