Hepatic Hypoxia-Inducible Factor 1a Mediates Ferroptosis via Transferrin Receptor 1 in Acute Liver Injury
Acute liver injury (ALI) is a potentially life-threatening condition lacking effective clinical drugs. Hypoxia-inducible factor-1a (HIF-1a) is a key regulator of both inflammation and metabolism. In ALI, HIF-1a expressions are upregulated, but the role of HIF-1a in hepatocytes and whether it can be targeted remain unclear. Herein, clinical samples and ALI murine models including lipopolysaccharide/D-galactosamine (LPS/D-GalN), acetaminophen (APAP), and thioacetamide (TAA) revealed an increase in HIF-1a expression and ferroptosis. Using HIF-1a gain and loss of function mouse and hepatocyte culture models, we demonstrated that HIF-1a upregulation exacerbated liver ferroptosis and injury. Mechanistically, HIF-1a/transferrin receptor protein 1 (TFR1) axis drives hepatic iron overload, promoting ferroptotic cell death and liver injury. In addition, TFR1 inhibition reversed HIF-1a-induced ALI. Importantly, pharmacological inhibition of HIF-1a and TFR1 significantly reduced ferroptosis and mitigated liver injury both in vivo and in vitro. Together, our findings demonstrate the pathological role of hepatic HIF-1a, which may serve as a promising target of therapeutic intervention. Overall design: RNA Seq profiling of hepatic HIF1a overexpression or wild type mouse livers in control gourps and LPS/D-GalN-treated groups.