Schematic diagram of proposed pathways. Down-regulation of cytokine-induced (ie, IL-6) hepcidin expression by CO involves 2 distinct and separable mechanisms: the inhibition of STAT-1/3 activation through a SOCS-3–dependent mechanism and the inhibition of CREBH maturation. CO can exert a suppressive effect on ER-stress–induced hepcidin expression in vitro and in the mouse model. CO also regulates hepcidin expression in part via ERK1/2 regulation induced by BMP signaling.