Fig. 6. Schema of cystathione β-synthase–mediated activation of HIF and PHD2 through persulfidation.

PHD2 is targeted by H₂S under normoxia to maintain its prolyl hydroxylation activity to degrade HIF-1α by VHL-mediated ubiquitin-proteasome pathway. Inhibition of CBS depletes endogenous H₂S level and stabilizes HIF-1α by inhibiting PHD2 activity in normoxia. Mechanistically, PHD2 is persulfidated by CBS and persulfidation of PHD2 at zinc finger domain augments activation in normoxia.