Pharmacological activation of FXR restores hepatic Steap3 expression during iron overload through direct transcriptional regulation in mice

Farnesoid X receptor (FXR) is a central regulator of hepatic metabolic homeostasis, and emerging evidence implicates FXR in iron-induced liver injury. Six-transmembrane epithelial antigen of the prostate 3 (STEAP3) is a ferrireductase involved in cellular iron processing, but its upstream regulation in the liver is poorly understood. Here, we identify mouse hepatic Steap3 as a previously unrecognized direct transcriptional target of FXR. Analysis of STEAP family expression showed that STEAP3 is highly expressed in both human and mouse liver tissues. In three mouse models, hepatic Steap3 was the only STEAP family member consistently suppressed by iron overload. Notably, Fxr deficiency in mice reduced basal hepatic Steap3 expression and attenuated iron-mediated Steap3 repression, whereas FXR activation by GW4064 induced Steap3 expression and partially restored its expression under iron-overload conditions. Further ChIP-seq analyses and luciferase reporter assays demonstrated that mouse Steap3 is a direct transcriptional target gene of FXR. Human transcriptomic, ChIP-seq, and motif analyses suggested that human STEAP3 may be regulated by FXR in human liver cells, although the FXR-binding signal near the STEAP3 promoter appeared relatively weak. Together, these findings establish Steap3 as a direct FXR target gene in mouse liver and suggest that FXR-dependent regulation of hepatic ferrireductase expression may represent a previously underappreciated component of the hepatic response to iron overload.