FIG 11.

Distinct levels of HO-1 gene regulation by the NRF2-mediated stress response and NRF2-independent substrate induction. The HO-1–DsRed reporter system revealed two levels of HO-1 gene expression regulation by different HO-1 inducers. Whereas CBD, CoCl₂, and representative electrophilic NRF2 inducers (DEM, CDDO-Im, CDDO-2P-Im, and CDDO-3P-Im) activate the HO-1 gene in an NRF2-dependent manner, the HO-1 substrate hemin induces HO-1 expression independent of NRF2. The activating transcription factors that contribute to hemin-mediated HO-1 induction are currently unknown.