# Hepatic Hypoxia-Inducible Factor 1α Mediates Ferroptosis via Transferrin Receptor 1 in Acute Liver Injury

## TL;DR

This study shows that HIF-1α promotes liver damage through ferroptosis and targeting it could help treat acute liver injury.

## Contribution

The study identifies HIF-1α as a mediator of ferroptosis via TFR1 in acute liver injury, offering a new therapeutic target.

## Key findings

- HIF-1α upregulation worsens liver ferroptosis and injury in multiple ALI models.
- The HIF-1α/TFR1 axis causes iron overload and ferroptotic cell death in the liver.
- Pharmacological inhibition of HIF-1α and TFR1 reduces ferroptosis and liver injury.

## Abstract

Acute liver injury (ALI) is a potentially life-threatening condition lacking effective clinical drugs. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of both inflammation and metabolism. In ALI, HIF-1α expressions are upregulated, but the role of HIF-1α 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-1α expression and ferroptosis. Using HIF-1α gain and loss of function mouse and hepatocyte culture models, we demonstrated that HIF-1α upregulation exacerbated liver ferroptosis and injury. Mechanistically, HIF-1α/transferrin receptor protein 1 (TFR1) axis drives hepatic iron overload, promoting ferroptotic cell death and liver injury. In addition, TFR1 inhibition reversed HIF-1α-induced ALI. Importantly, pharmacological inhibition of HIF-1α 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-1α, which may serve as a promising target of therapeutic intervention.