Fig. 1

Activation and degradation of HIFα. Under normoxic conditions, PHD uses 2-OG as a substrate and ascorbic acid and Fe²⁺ as co-substrates to catalyse the oxygen-dependent hydroxylation (OH) of HIFα (both HIF-1α and HIF-2α). Oxygen-dependent hydroxylation leads to the recognition of HIFα by the pVHL tumour suppressor, which recruits the E3 ubiquitin ligase, resulting in the ubiquitination and protease degradation of HIFα. Under hypoxia, the hydroxylation of HIFα is inhibited, leading to the stabilization of HIFα. HIFα dimerizes with HIF-1β to form a transcriptional activation complex, which binds to the HRE in the promoter region of target genes, inducing their transactivation