Using a zebrafish model for hepatoerythropoietic porphyria(HEP),we recently observed exocrine pancreas-specific downregulation of six zymogens in the HEP zebrafish(yquem/urod,-/-).However,the molecular mechanism underlying heme regulation of these exocrine zymogens is unclear.Here we show that zebrafish bach1b,nrf2a and mafK are all expressed in the zebrafish exocrine pancreas.Overexpression of bach1b and knockdown of nrf2a result in downregulation of these zymogens,whereas overexpression of nrf2a and knockdown of bach1b cause their upregulation.In vitro luciferase assays demonstrated that heme activates these zymogens in a dosage-dependent manner,and the zymogens promoter activities require the integral MARE(Maf Recognition Element)motif.The Bach1b:MafK heterodimer represses these zymogens,whilst the Nrf2a:MafK heterodimer activates them.Furthermore,EMSA shows that MafK binds the MARE sites in the 5’ regulatory regions of these zymogens.ChIP assays show that heme triggers replacing Bach1b with Nrf2a within the MafK-occupied MARE sites in the regulatory regions of these zymogens,and particularly in heme-deficient porphyria,the repressing Bach1b:MafK heterodimer dominates,which can be switched to the activating Nrf2a:MafK heterodimer by hemin treatment.These results provide novel insights into porphyria pathogenesis,and new approaches to diagnosing and treatment of porphyria patients.